Download position stand on androgen and human growth hormone use

POSITION STATEMENT
POSITION STAND ON ANDROGEN
GROWTH HORMONE USE
AND
HUMAN
JAY R. HOFFMAN,1 WILLIAM J. KRAEMER,2,3 SHALENDER BHASIN,4 THOMAS STORER,4,5
NICHOLAS A. RATAMESS,1 G. GREGORY HAFF,6 DARRYN S. WILLOUGHBY,7 AND ALAN D. ROGOL8,9
1
Department of Health and Exercise Science, The College of New Jersey, Ewing, New Jersey 08628; 2Department of Kinesiology;
Department of Physiology and Neurobiology, The University of Connecticut, Storrs, Connecticut 06269; 4Section of
Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston Medical Center, Boston, MA;
5
Department of Kinesiology, Division of Health Sciences, El Camino College, Torrance California; 6Division of Exercise
Physiology, Department of Human Performance and Applied Exercise Sciences, West Virginia University, Morgantown,
West Virginia 26508; 7Department of Health, Human Performance, and Recreation, Baylor University, Waco, Texas 76798;
8
Department of Pediatrics, University of Virginia, Charlottesville, Virginia; and 9Department of Pediatrics, Riley Hospital,
Indiana University School of Medicine, Indianapolis, Indiana
3
ABSTRACT
Hoffman, JR, Kraemer, WJ, Bhasin, S, Storer, T, Ratamess, NA,
Haff, GG, Willoughby, DS, and Rogol, AD. Position stand on
Androgen and human growth hormone use. J Strength Cond
Res 23(5): S1–S59, 2009—Perceived yet often misunderstood
demands of a sport, overt benefits of anabolic drugs, and the
inability to be offered any effective alternatives has fueled
anabolic drug abuse despite any consequences. Motivational
interactions with many situational demands including the desire
for improved body image, sport performance, physical function,
and body size influence and fuel such negative decisions.
Positive countermeasures to deter the abuse of anabolic drugs
are complex and yet unclear. Furthermore, anabolic drugs work
and the optimized training and nutritional programs needed to
cut into the magnitude of improvement mediated by drug abuse
require more work, dedication, and preparation on the part of
both athletes and coaches alike. Few shortcuts are available
to the athlete who desires to train naturally. Historically, the
NSCA has placed an emphasis on education to help athletes,
coaches, and strength and conditioning professionals become
more knowledgeable, highly skilled, and technically trained in
their approach to exercise program design and implementation.
Optimizing nutritional strategies are a vital interface to help
cope with exercise and sport demands (516–518). In addition,
research-based supplements will also have to be acknowledged as a strategic set of tools (e.g., protein supplements
before and after resistance exercise workout) that can be used
in conjunction with optimized nutrition to allow more effective
adaptation and recovery from exercise. Resistance exercise is
Address correspondence to Jay R. Hoffman, [email protected].
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the most effective anabolic form of exercise, and over the past
20 years, the research base for resistance exercise has just
started to develop to a significant volume of work to help in the
decision-making process in program design (187,248,305).
The interface with nutritional strategies has been less studied,
yet may yield even greater benefits to the individual athlete in
their attempt to train naturally. Nevertheless, these are the 2
domains that require the most attention when trying to optimize
the physical adaptations to exercise training without drug use.
Recent surveys indicate that the prevalence of androgen use
among adolescents has decreased over the past 10–15 years
(154,159,246,253,370,441,493). The decrease in androgen
use among these students may be attributed to several factors
related to education and viable alternatives (i.e., sport supplements) to substitute for illegal drug use. Although success has
been achieved in using peer pressure to educate high school
athletes on behaviors designed to reduce the intent to use
androgens (206), it has not had the far-reaching effect desired.
It would appear that using the people who have the greatest
influence on adolescents (coaches and teachers) be the
primary focus of the educational program. It becomes imperative
that coaches provide realistic training goals for their athletes and
understand the difference between normal physiological
adaptation to training or that is pharmaceutically enhanced.
Only through a stringent coaching certification program will
academic institutions be ensured that coaches that they hire will
have the minimal knowledge to provide support to their athletes
in helping them make the correct choices regarding sport
supplements and performance-enhancing drugs.
The NSCA rejects the use of androgens and hGH or any
performance-enhancing drugs on the basis of ethics, the ideals
of fair play in competition, and concerns for the athlete’s health.
The NSCA has based this position stand on a critical analysis of
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the scientific literature evaluating the effects of androgens and
human growth hormone on human physiology and performance. The use of anabolic drugs to enhance athletic
performance has become a major concern for professional
sport organizations, sport governing bodies, and the federal
government. It is the belief of the NSCA that through education
and research we can mitigate the abuse of androgens and hGH
by athletes. Due to the diversity of testosterone-related drugs
and molecules, the term androgens is believed to be a more
appropriate term for anabolic steroids.
1. Androgen administration in a concentration-dependent
manner increases lean body mass, muscle mass, and
maximal voluntary strength in men. However, the upper
concentration for maximum effects remains unknown.
2. Combined administration of androgens and resistance
exercise training is associated with greater gains in lean
body mass, muscle size, and maximal voluntary strength in
men than either intervention alone.
3. Testosterone therapy is approved only for the treatment
of hypogonadism in adolescent and adult men. However,
the anabolic applications of androgens and selective AR
modulators are being explored for the functional limitations
associated with aging and some types of chronic illness.
4. The magnitude and frequency of adverse effects among
androgen users have not been systematically studied.
Potential adverse effects of androgen use in men include
suppression of the hypothalamic-pituitary-gonadal axis,
mood and behavior disorders, increased risk of cardiovascular
disease, hepatic dysfunction with oral androgens, insulin
resistance, glucose intolerance, acne, gynecomastia, and
withdrawal after discontinuation. In addition, the polypharmacy of many androgen users (psychoactive and accessory
drugs) may have serious adverse effects of their own.
5. The adverse effects of androgen administration in women
are similar to those noted in men. In addition, women
using androgens may also experience virilizing side effects
such as enlargement of the clitoris, deepening of the voice,
hirsutism, and changes in body habitus. These changes
may not be reversible on cessation of androgen use.
6. In pre- and peripubertal children, androgen use may lead to
virilization, premature epiphyseal closure, and resultant
adult short stature.
7. Since 1990, the use of androgens for a nonmedical purpose
is illegal. Androgens are labeled as a schedule III drug.
Possession of any schedule III substance including
androgens is punishable by fine, prison time, or both.
Prescribing androgens for bodybuilding or enhanced
athletic performance is also punishable as noted above.
8. Human growth hormone increases lean body mass within
weeks of administration; however, the majority of the change
is within the water compartment and not in body cell mass.
9. Human growth hormone is unlikely to be administered as
a single agent but often in combination with androgens.
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10. Combined administration of hGH and resistance exercise
training is associated with minimal gains in lean body
mass, muscle size, and maximal voluntary strength in men
compared with resistance exercise alone.
11. Human growth hormone is approved for the therapy of
children and adolescents with growth hormone deficiency, Turner syndrome, small for gestational age with
failure to catch-up to the normal growth curves, chronic
kidney disease, Prader-Willi syndrome, idiopathic short
stature, Noonan syndrome, and SHOX gene deletion. For
adults, hGH is approved for the treatment of GH
deficiency, AIDS/HIV with muscle wasting, and short
bowel syndrome.
12. The magnitude and frequency of adverse events associated with hGH use are clearly dose related. Potential
adverse events include suppression of the hypothalamicpituitary GH/IGF-1 axis, water retention, edema, increased intracranial pressure, joint and muscle aches, and
those of needle injection (hepatitis and HIV/AIDS).
These should be the same in women as well as in men.
13. Continued effort should be made to educate athletes,
coaches, parents, physicians, and athletic trainers along
with the general public on androgen and hGH use and
abuse. Educational programs should focus on potential
medical risks of these illegal performance-enhancing
drugs use, optimizing training programs and concurrent
nutritional strategies to enhance physiological adaptation
and performance. In addition, educating coaches on
setting realistic training goals and expectations for their
athletes will help reduce the pressures to use illegal PED
and assist in potentially identifying potential users of
illegal PED.
14. The NSCA supports and promotes additional research
funding to be directed toward effective educational
programs, documentation of both acute and long-term
adverse effects of androgen and hGH abuse, strategies for
optimizing athletic performance through training and
nutritional interventions, strategies to help athletes
discontinue androgen and hGH use, and strategies for
the detection of abuse of androgens and hGH.
T
he use of androgens by athletes has received a lot of
attention in the media over the past decade. The
current media attention to this topic has falsely
suggested that androgen use by athletes is
a relatively new phenomenon. It contrast, it is something
that has been around for many decades. For the past half
century, the use of androgens by athletes has increased
medical and scientific focus on the efficacy and dangers of
these compounds. The medical risks associated with
androgens as well as ethical considerations have led the
major sport governing bodies to initiate measures to combat
their use. All major national and international sport
organizations have banned androgens from use by their
athletes, and detection of use results in suspension from
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competition. Although educational and awareness programs
have been developed to combat the use of androgens, the
efficacy of these programs is not clear. Considering that most
athletes and coaches are aware of the potential side effects and
risks associated androgens use, including the risk of becoming
barred from competition, they still continue to search for
ways to mask their use to avoid detection or have redirected
their efforts to use anabolic drugs that are not detectable (e.g.,
human growth hormone [hGH]).
A number of position stands and review papers have been
written on this subject. However, the information contained
in these reviews is often outdated, incorrect, or incomplete.
Previous position stands published by the National Strength
and Conditioning Association (NSCA) and the American
College of Sports Medicine (ACSM) are more than 15–20
years old. In light of the intense media scrutiny that has been
recently focused on these performance-enhancing drugs, it
appears that an updated review and examination of this issue
are required. It is acknowledged that there are other
performance-enhancing drugs that are presently being used
by athletes (e.g., erythropoietin [EPO], insulin, thyroid
hormone). However, this report will focus on the most
widely publicized drugs: androgens and hGH. The important
clinical use of these drugs will be discussed as well. Each
of these drugs will be examined separately, with specific
emphasis on their physiological role, history of use, research
on the efficacy as a performance-enhancing drug, medical
issues associated with their use, and when applicable, dosing
patterns, frequency of use, detection methods, masking
agents, and other drugs that are commonly used concomitantly with these anabolic agents. In addition, legal issues
associated with these performance-enhancing drugs,
direction of future research, and performance-enhancing
drug education programs will be discussed.
ANDROGENS
Androgen is a sex hormone that promotes the development
and maintenance of the male sex characteristics. Testosterone
is the principal secreted androgen in men. Androgens have
both masculinizing (development of male secondary sex
characteristics, including hair growth) and anabolic effects
(increase in skeletal muscle mass and strength). For decades,
pharmaceutical companies have attempted to develop
androgens that have preferential anabolic activity and
reduced or no androgenic (masculinizing) activity; these
compounds have been referred to as anabolic steroids.
However, there are few clinical trial data in humans to
support the view that such compounds are purely anabolic;
the steroidal compounds available to date have both
androgenic and anabolic activities. A number of terms—
anabolic steroids, androgenic steroids, anabolic-androgenic
steroids, and androgens—have been used in literature to
describe these androgen derivatives. For the sake of
uniformity and accuracy, we have used the term ‘‘androgen’’
to describe these compounds that bind androgen receptor
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(AR) and exert masculinizing as well as anabolic effects to
varying degrees.
What Is the Physiological Role of Testosterone?
Testosterone is a 19-carbon steroid (Figure 1) with a ketone
group at position 3, hydroxyl group at position 17, and
a double bond at position 4. Its basic structure is composed of
3 cyclohexane rings and 1 cyclopentane ring with a methyl
group at positions 10 and 13 (472). The biosynthesis of
testosterone begins in the adrenal cortex where cholesterol
is converted through a multistep process to dehydroepiandrosterone (DHEA) and androstenedione. The androgens
androstenediol and androstenedione are natural testosterone
precursors. The biosynthesis of testosterone takes place
within the testicular Leydig cells in 2 metabolic pathways.
During the progesterone pathway (delta-4 pathway),
pregnenolone is metabolized to progesterone by the 3beta-hydroxysteroid dehydrogenase and an isomerase. Progesterone is then converted to 17-alpha-hydroxyprogesterone by 17-alpha-hydroxylase and C17:C21-lyase to
androstenedione, then to testosterone by reduction of the
17-keto group by 17-beta-hydroxysteroid dehydrogenase.
The DHEA pathway (delta-5 pathway) leads from pregenolone to 17-alpha-hydroxypregnenolone to DHEA and is
then converted to 5-delta-androstenediol by C17:C21-lyase.
Testosterone and the other C-19 androgens can also be
converted into the compound dihydrotestosterone (DHT) or
into estradiol by the action of the enzyme aromatase (Figure 2).
In males, more than 95% of testosterone is secreted by the
Leydig cells under the control of luteinizing hormone (LH).
The remainder is produced via conversion in the adrenal
cortex. This is a major way in which females produce
testosterone in addition to the ovaries (although testosterone
concentrations are much lower in women). Healthy men
produce approximately 4.0–9.0 mg of testosterone per day
with blood concentrations ranging from 300 to 1,000 ngdL21
(10.4–34.7 nmolL21), whereas for females blood concentrations range from 15 to 65 ngdL21 (0.5–2.3 nmolL21)
(38,59). Dihydrotestosterone is mostly formed via peripheral
conversion in other target (non-skeletal muscle) tissues via the
enzyme 5a-reductase, an enzyme that converts testosterone to
DHT in the cytoplasm. Once secreted, testosterone travels
through the circulation either free (i.e., free testosterone) or
bound to a carrier protein. About 35–38% of testosterone
travels bound to albumin, with the remaining bound to the
glycoprotein sex hormone–binding globulin (SHBG) (472).
According to the free hormone hypothesis, it is only the free
testosterone that is bioavailable and able to diffuse through the
cell membrane and bind to its cytosolic receptor, or perhaps
bind to some membrane receptor (414). However, recent
evidence that SHBG-bound testosterone may also be internalized through the megalin family of proteins and be
biologically active (225,367). There is a growing body of
evidence that albumin-bound testosterone may dissociate in
many organs such as the liver and brain and become
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Figure 1. Testosterone synthesis.
biologically available (356,432). Only about 0.5–2.5% of
circulating testosterone is in the free form. Thus, free
testosterone concentration is a function of total testosterone
concentration and binding protein concentration. Testosterone plays a number of important roles in the human body.
Testosterone affects many physiological systems, which are
listed in Table 1. It is believed that most actions of testosterone
are dependent on total circulating concentrations and directly
produced via testosterone’s interaction with the AR. The
increase in gene transcription and translation of proteins elicits
several changes that enhance muscle hypertrophy, strength,
endurance, and power (285,287,458). In addition, testosterone
has been suggested to lead to muscle anabolism via
antiglucocorticoid actions (i.e., testosterone may bind with
high affinity to cortisol receptors, thereby attenuating potential
catabolic actions or inhibit glucocorticoid action via crossregulation with ARs), potentiation of muscle insulin-like
growth factor-1 (IGF-1), and attenuation of myostatin action
and signaling (38,285,546). Last, testosterone plays a key role
in development of secondary sex characteristics, for example
genital growth during puberty, deepening of the voice, hair
growth, and so on.
Feedback Control of Testosterone Synthesis and Secretion. Control
of testosterone synthesis and secretion begins in the
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hypothalamus, which links the nervous and endocrine
systems and secretes several regulatory hormones that act
on the anterior pituitary gland to either increase or inhibit
hormonal release. One hormone secreted by the hypothalamus is gonadotropin-releasing hormone (GnRH). Gonadotropin-releasing hormone is secreted in pulses every 90–120
minutes and binds to gonadotropes in the anterior pituitary
where it stimulates the secretion of LH. Luteinizing hormone
secreted into circulation binds to receptors on Leydig cells of
the testes where it stimulates testosterone secretion. Testosterone elevations, via negative feedback, eventually will
reduce further testosterone secretion via direct inhibition at
the hypothalamic and anterior pituitary axis. Much of the
inhibition stems from peripheral aromatization of testosterone to estradiol. Estradiol elevations feedback directly to the
hypothalamus, thereby reducing secretion of GnRH and
subsequently LH from the anterior pituitary. Androgens use
negative feedback on the hypothalamic-pituitary axis such
that the body’s own endogenous testosterone production is
minimized. Thus, during exogenous androgen use, testicular
shrinkage may ensue. The adverse effects associated with
androgen use have prompted many athletes to use endogenous testosterone enhancers when coming off of androgen
cycles. This will be discussed in more detail later in this report.
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Figure 2. Basic synthesis of dihydrotestosterone and the estrogens: estradiol, estrone, and estriol.
Mechanisms of Testosterone Effects on the Skeletal Muscle.
Testosterone-induced increase in skeletal muscle mass is
associated with hypertrophy of both type I and type II fibers
(470) and an increase in the number of myonuclei and
satellite cells (491). Testosterone promotes the differentiation
of mesenchymal multipotent cells into the myogenic lineage
and inhibits their differentiation into the adipogenic lineage
(515,532). Androgens regulate mesenchymal multipotent
cell differentiation by binding to AR and promoting the
association of AR with b-catenin and translocation of the
AR–b-catenin complex into the nucleus, resulting in
activation of T-cell factor 4 (TCF-4) (548). The activation
of TCF-4 modulates a number of Wnt-regulated genes that
promote myogenic differentiation and inhibit adipogenic
differentiation (548).
Testosterone also inhibits preadipocyte differentiation into
adipocytes (548). The effects of testosterone on myogenic
differentiation in vitro are blocked by the AR antagonist,
bicalutamide, indicating that these effects are mediated
through an AR pathway (548). It is possible that androgens
might exert additional effects through nongenomic mechanisms. Testosterone increases fractional muscle protein
TABLE 1. General effects of androgens in non–sex-linked tissues.
Increases lean body mass
Increases cardiac tissue mass
Decreases body fat percentage
Increases isometric and dynamic muscle strength and power
Enhances recovery ability between workouts
Increases protein synthesis, accretion, and nitrogen retention (and possible anticatabolism)
Increases muscle cross-sectional area
Stimulates growth of the epiphyseal plate
Increases erythropoiesis, hemoglobin, and hematocrit
Increased vasodilation
Increases bone mineral content, density, and markers of bone growth
Regulation of osteoblasts, bone matrix production, and organization
Increases glycogen and creatine phosphate storage
Increases lipolysis and low-density lipoproteins and decreases high-density lipoproteins
Increases neural transmission, neurotransmitter release, myelinization, and regrowth of damaged peripheral nerves
Repression of myostatin
Behavior modification (i.e., aggression)
Acute elevations in skeletal intramuscular calcium concentrations
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synthesis and improves the reutilization of amino acids by the
muscle (448,506).
Androgen Receptor. Classical genomic actions of androgens
are mediated through the AR. The AR gene is located on the
long q arm of chromosome X at position 11–12 and contains
8 exons coding for the N-terminus, central DNA binding, and
C-terminal ligand-binding domains (199,375). The first
exon contains several regions of repetitive DNA sequences
including the CAG triplet repeats (313). The length of this
sequence is variable and long CAG repeats interfere with
androgen actions, whereas short repeats enhance androgen
action. The AR is a 110-kDa receptor consisting of 919 amino
acids, 12 a-helices, and 2 b-sheets that belong to a large
family of nuclear transcription factors. A truncated AR protein
(87 kDa) with similar function has also been identified (532).
Studies have shown that ARs are located in virtually all tissues
except in the spleen and adrenal medulla (393,491).
Free testosterone diffuses through the cell membrane and
binds to the C-terminal ligand-binding domain, causing dissociation of the AR from a group of heat shock proteins in the
cytoplasm. Testosterone binding to AR results in conformational changes in the AR protein, recruitment of tissuespecific coregulators, and translocation of liganded complex
into the nucleus where it binds the androgen response
elements of AR target genes (161,548). Considering that
skeletal muscle contains little 5a-reductase, testosterone is
the primary ligand (not DHT) inducing transcription. In
addition, the N-terminal region is the primary site for
interaction with large families of coregulators that function
to amplify the transcriptional signal and mediate AR action
(157). Coregulator binding forms a bridge between the DNAbound AR and the transcriptional machinery, thereby
modulating transcription and tissue selectivity. Approximately 300 coregulators have been identified (523).
Androgen binding stabilizes the AR (547,548). The half-life
of AR without androgen binding is 1 hour, whereas the ARandrogen complex extends the half-life to 6 hours (287).
Androgens slow AR degradation by prolonging nuclear
retention. Testosterone (the primary androgen interacting
with ARs in skeletal muscle) dissociates from the AR 3 times
faster than DHT or synthetic androgens and is less effective
for stabilizing the AR (547). However, similar stabilizing
effects occur with larger doses of testosterone in comparison
with lesser dosages of DHT (287,547). Thus, it appears AR
stabilization is dose dependent. The AR is capable of
undergoing multiple bouts of recycling between the nucleus
and the cytoplasm after ligand binding and dissociation (427).
Upregulation of AR content is affected by other hormonereceptor interactions including IGF-I, growth hormone
(GH), and triiodothyronine, whereas glucocorticoids and
estrogens downregulate AR messenger RNA (mRNA)
(97,161,169,322,419).
The AR concentration in skeletal muscle depends on
several factors including fiber type, contractile activity (e.g.,
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resistance training), nutritional supplementation, and the
concentrations of testosterone (31,84,155,307,415). Resistance training upregulates AR content within a few days after
a workout (31). However, the initial response may be downregulation (415) unless nutritional (e.g., protein, carbohydrate) interventions are applied (307). The regulation of AR
mRNA by androgens varies with androgen dose duration and
mode of administration (16,169,306,308,331,355,380,448).
Long-term exposure to high concentrations of androgens
may downregulate AR content in some tissues (83).
Nongenomic Actions of Testosterone. Although most actions of
testosterone are mediated within the cytoplasm via the AR,
some studies have suggested that some rapid actions of
testosterone (i.e., that take place within seconds or minutes)
may be mediated via nongenomic activity (414). Evidence
supporting nongenomic actions has been attained from
studies showing these actions of testosterone to occur despite
either cytosolic AR inhibition or administration of a testosterone molecule unable to diffuse across the cell membrane
(170). For example, nongenomic actions of testosterone have
been identified to occur in Sertoli cells, hypothalamus,
anterior pituitary, prostate, osteoblasts, immune cells, cardiovascular tissues, and skeletal muscle (170,414). In skeletal
muscle, testosterone administration has been shown to
rapidly (within minutes) increase intramuscular calcium and
extracellular signal–regulated kinase 1/2 (ERK 1/2) phosphorylation (a class of mitogen-activated protein kinase and
an intermediate involved in muscle hypertrophy) (170).
Similar intramuscular calcium increases have been reported
in cardiac myocytes after testosterone administration (515).
It has been suggested that these nongenomic actions of
testosterone may be mediated by a membrane-bound AR
(coupled to a G-protein–linked second messenger system)
(170) or perhaps by a membrane-bound SHBG receptor for
non–free testosterone still bound to SHBG (414). However,
a membrane receptor for testosterone has not yet been
isolated and the evidence for nongenomic actions remains
inconclusive.
Testosterone Metabolism. In addition to peripheral conversion to
DHTand estradiol, testosterone is inactivated by the liver and
excreted in urine via 2-phase metabolism. In phase 1
metabolism, the liver converts most circulating testosterone
(and other androgens) to various inactive metabolites via
enzymatic oxidation, reduction, and hydroxylations to the
A, B, C, and D rings (437). The major urinary metabolites of
testosterone, androsterone and etiocholanolone, are formed
via the enzyme 17b-hydroxy dehydrogenase and are
excreted as 17-ketosteroids. Phase 2 reactions in the liver
and/or kidneys include conjugation of phase 1 metabolites
with either glucuronic acid or sulfuric acid. Conjugation
reactions are enzymatically controlled (e.g., UDPglucuronosyltransferase enzymes) (48). Not all androgens
are excreted as conjugates, some are unconjugated including
oxandrolone and some metabolites of stanozolol (437).
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Detection of androgens or their metabolites in the urine is the
basis of current drug testing.
Types of Androgens
Testosterone, when administered orally, has a short half-life
because of its first-pass presystemic metabolism. 17-Alpha
alkyl substitutions in the testosterone molecule render it less
susceptible to first-pass presystemic metabolism. However,
17-alpha alkylated derivatives are potentially hepatotoxic and
markedly suppress high-density lipoprotein (HDL) cholesterol levels. They are not recommended for clinical use.
Esterification of the 17-beta-hydroxyl group renders the
molecule more hydrophobic; testosterone esters such as
cypionate, undecanoate, and enanthate, when injected in an
oily suspension intramuscularly, are released slowly from the
hydrophobic oil depot into the general circulation, thus
extending their duration of action. The degree of hydrophobicity is related to the length of the ester side chain; the longer
esters such as cypionate and enanthate have more extended
duration of action than shorter esters such as propionate. The
de-esterification of testosterone esters is not rate limiting;
thus, the plasma half-life of testosterone esters is not significantly different from that of unesterified testosterone. The
long duration of action of testosterone esters is mostly due to
the slow release of the testosterone ester from the oily depot
in the muscle.
Slight biochemical modifications can alter biological
activity by modifying presystemic metabolism, half-life, AR
binding affinity, AR stabilization, coactivator recruitment,
nuclear translocation, DNA binding affinity, and tissue selectivity. Also, biochemical modifications may determine
whether the resulting molecule can undergo aromatization
or 5-a reduction. Only a limited amount of information is
available about the structure-activity relationships of the
testosterone molecule.
One of the first changes made to the testosterone molecule
was the addition of a methyl or ethyl group to the 17-alphacarbon position. This addition inhibits the presystemic
metabolism of the molecule, greatly extending its half-life
and making it active when administered orally. However,
orally administered 17-alpha alkylated androgens are potentially hepatotoxic and markedly lower plasma HDL cholesterol. 17-Alkyl substitution also lowers the interaction with
aromatase (148).
Because there are many agents in production and literally
hundreds more that have been synthesized, this discussion
focuses on the basics involving the steroid ring substitutions
and how these substitutions affect the properties of the drug.
Detailed analysis is limited to those agents that are available or
have been approved for use in the U.S.A. Table 2 provides
specific structure and chemical information on selected,
popular androgens (AAS).
Testosterone Esters. Testosterone esters have seen an increase in
their use in replacement therapy and in their propensity for
abuse. The testosterone esters all have the testosterone
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molecule with a carboxylic acid group (ester linkage) attached
to the 17-b hydroxyl group in common. These esters differ in
structural shape and size and function only to determine the
rate at which the testosterone is released from tissue. Larger
esters are released into the bloodstream more slowly, as the
ester decreases the solubility of the steroid in water and
increases its fat solubility. When a steroid has an ester
attached, the steroid is rendered inactive because the ester
prevents it from binding to a receptor. For the steroid to
become active again, the enzyme esterase must detach the
ester and restore the hydrogen to form the hydroxyl group
attached to C-17. Once the molecule is converted back to
testosterone, it is able to bind to a receptor and is an active
steroid. Esters, as mentioned earlier, are usually attached at
C-17, although they are sometimes found at C3. Generally,
the shorter the ester chain, the shorter the half-life and quicker
the drug enters circulation. Longer/larger esters usually have
a longer half-life and are released into the circulation more
slowly. Once in the circulation, the ester is cleaved, leaving
free testosterone. Common testosterone preparations include
testosterone propionate, testosterone cypionate, and testosterone enanthate.
In testosterone cypionate, the hydrogen from the hydroxyl
group on C-17 has been removed and replaced with an
8-carbon side chain containing 1 cyclopentane ring and 1
carbonyl (=O) group. This is one of the larger esters of
testosterone. In order of size, from smallest molecular weight
to largest, the esters of testosterone are acetate, propionate,
phenylpropionate, isocaproate, caproate, enanthate, cypionate, decanoate, undecylenate, undecanoate, and laurate. The
largest of these esters, laurate, contains 12 carbon atoms, 24
hydrogen atoms, and 2 oxygen atoms. These esters can be
attached to other steroids as well and are not limited to
testosterone.
Common Testosterone Derivatives. The development of androgens was apparently centered on the need for drugs that
exhibited characteristics different from those of testosterone.
In general, the goal was to develop drugs that were more
anabolic and less androgenic than testosterone, capable of
being administered orally, and had less effect on the
hypothalamic-pituitary-gonadal axis. Most androgens are
derived from 3 compounds: testosterone, DHT, and
19-nortestosterone. The latter compound is structurally
identical to testosterone except for the deletion of the 19th
carbon, thereby resulting in its name. These parent compounds offer different properties with regard to action and
metabolism that are generally constant throughout the entire
family of compounds.
Methyltestosterone. Methyltestosterone (Metesto, Android) is a very basic androgen with the only addition being
a methyl group at C-17. This eliminates first-pass degradation
in the liver, making oral dosing possible. It also causes doserelated hepatotoxicity. It is metabolized by aromatase to the
estrogen, 17-alpha methyl estradiol, and is also reduced by 5-a
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TABLE 2. Types of anabolic steroids; structure and chemical properties.
Name of Androgen
Chemical structure
Testosterone esters
Testosterone cypionate
17-b-hydroxy-4-androsten-3-one
Testosterone base + cypionate ester
Formula: C27H40O3
Molecular weight: 412.6112
Molecular weight (base): 288.429
Molecular Weight (ester): 132.1184
Formula (base): C19H28O2
Formula (ester): C8H14O2
Melting point (base): 155
Melting point (ester): 98–104°C
Effective dose (men): 300–2000 mg+ week
Effective dose (women): not recommended
Active life: 15–16 d
Detection time: 3 m
Anabolic to androgenic ratio: 100:100
17-b-hydroxy-4-androsten-3-one
Testosterone base + enanthate ester
Molecular weight: 412.6112
Molecular weight (base): 288.429
Molecular weight (ester): 130.1864
Formula (base): C19H28O2
Formula (ester): C7H12O
Melting point (base): 155
Effective dose (men): 300–2000 mg+ week
Effective dose (women): not recommended
Active life: 15 d
Detection time: 3 mo
Anabolic to androgenic ratio: 100:100
4-Androstene-3-one, 17beta-ol
Testosterone base + propionate ester
Molecular weight (base): 288.429
Molecular weight (ester): 74.0792
Formula (base): C19H28O2
Formula (ester): C3H6O2
Melting point (base): 155
Melting point (ester): 21°C
Effective dose (men): 350—2,000 mg+ week
Effective dose (women): 50–100 mgwk21
Active life: 2–3 days
Detection time: 2–3 weeks
Anabolic to androgenic ratio: 100:100
Testosterone enanthate
(Primoteston)
Testosterone propionate
Common testosterone derivatives
Methyltestosterone
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[17alpha-methyl-4-androstene-3-one,17b-ol]
Molecular weight: 302.4558
Formula: C20H30O2
Melting point: 162–167°C
Effective dose: 25–100 mg/day21(men);
not applicable in women
Active life: 6–8 h
Detection time: 4–6 wk
Anabolic to androgenic ratio (range): 94—130:115–150
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Methandrostenolone
(Dianabol)
Fluoxymesterone
(Halotestin)
Common nandrolone derivatives
Nandrolone decanoate
(Deca-Durabolin)
Ethylestrenol
(Maxibolin, Orabolin)
Trenbolone
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[17a-methyl-17b-hydroxy-1,4-androstadien-3-one]
Molecular weight: 300.44
Formula: C20H28O2
Melting point: N/A
Effective dose: 25–50 mg (as low as 10 and
as high as 100 have been reported)
Active life: 6–8 h
Detection time: up to 6 wk
Anabolic to androgenic ratio (range): 90–210:40–60
[9-alpha-fluoro-11-beta-hydroxy-17-alpha-methyl4-androstene-3-one,17b-ol]
Molecular weight: 336.4457
Formula: C20H29FO3
Melting point: 240°C
Effective dose: 10–40 mg/d
Active life: 6–8 h
Detection time: 2 mo
Anabolic to androgenic ratio: 1,900:850
(Nandrolone base + decanoate ester)
[19-nor-androst-4-en-3-one-17beta-ol]
Molecular weight (base): 274.4022
Molecular weight (ester): 172.2668
Formula (base): C18H26O2
Formula (ester): C10H20O2
Melting point (base): 122–124°C
Melting point (ester): 31–32°C
Effective dose (men): 200–600 mgwk21
(2mglb21of bodyweight)
Effective dose (women): 50–100 mgw21
Active life: 15 d
Detection time: Up to 18 mo
Anabolic to androgenic ratio: 125:37
[19-Nor-17alpha-pregn-4-en-17-ol]
Formula: C20H22O
Molecular weight: 288.46
Melting point: 76–78°C
Effective dose (men): 40 mg (?)
Effective dose (women): 10 mg (?)
Active life: 8–12 h
(17beta-hydroxyestra-4,9,11-trien-3-one)
(Trenbolone base + acetate ester)
Formula: C20H24O3
Molecular weight: 312.4078
Molecular weight (base): 270.3706
Molecular weight (ester): 60.0524
Formula (base): C18H22O2
Formula (ester): C2H4O2
Melting point (base): 183–186°C
Melting point (ester): 16.6°C
Effective dose (men): 50–150 mg ED
Effective dose (women): not recommended
Active life: 2–3 d
Detection time: 5 mo
Anabolic to androgenic ratio: 500:500
(Continued on next page)
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Common dihydrotestosterone derivatives
Oxandrolone (Anavar)
[17b-hydroxy-17a-methyl-2-oxa-5a-androstane-3-one]
Molecular weight: 306.4442
Formula: C19H30O3
Melting point: 235–238°C
Effective dose—men: 20–100 mgd21 (or .125 mgkg21
body weight); women: 2.5–20 mgd21
Active life: 8–12 h
Detection time: 3 wk
Anabolic to androgenic ratio (range): 322–630:24
[17beta-Hydroxy-17-methyl-5alpha-androstano [3,2-c]
pyrazole]
Molecular weight: 344.5392
Molecular formula: C22H36N2O
Melting point: N/A
Effective dose (men): 50–100 mgd21
Effective dose (women): 2.5–10 mgd21
Active life: 8 h
Detection time: 3 wk (oral) to 9 wk (injectable)
Androgenic to anabolic ratio: 30:320
[17 beta-hydroxy-2-hydroxymethylene-17 alpha-methyl-5
alpha-androstan-3-one]
Molecular formula: C21H32O3
Melting point: 178–180°C
Effective dose: 100 mg (optimal)
Active life: ,16 h
Detection time: up to 8 wk
Androgenic to anabolic ratio: 45:320
Molecular Formula: C21H32O3
Stanozolol (Winstrol)
Oxymetholone (Anadrol)
reductase to 17-alpha-methyl DHT. This compound appears
to exhibit very strong androgenic and estrogenic side effects,
and its use is generally avoided for these reasons.
Methandrostenolone. Methandrostenolone (Dianabol)
has an added cis-1 to cis-2 double bond in an attempt to
reduce both estrogenic and androgenic properties. However,
it does undergo aromatization to the estrogen, 17-alpha
methyl estradiol, but is reduced by 5-a reductase to adihydromethandrostenolone (475). This steroid was first
commercially manufactured in 1958 by Ciba under the brand
name Dianabol and quickly became the most used and
abused steroid worldwide to date. This agent is very anabolic
with a half-life of approximately 4 hours. The methyl group
at C-17 makes this anabolic-androgenic steroid an oral
preparation and potentially hepatotoxic. Both Ciba and
generic firms in the U.S.A. discontinued methandrostenolone
in the late 1980s, but more than 15 countries worldwide still
produce it in generic form.
Fluoxymesterone. Fluoxymesterone (Halotestin) is a
potent androgen that is a substrate for 5-a reductase for
conversion to DHT metabolites. With the addition of a 9fluoro group, it becomes an androgen with very little anabolic
activity; however, an added 11-b hydroxyl group inhibits its
aromatization. The C-17 methyl group makes oral
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administration possible but not without apparent hepatotoxicity. This drug does not appear to be favored in clinical
practice due to its poor anabolic effects, yet athletes typically
use it for its apparent androgenic nature and lack of peripheral
aromatization.
Common Nandrolone Derivatives. Nandrolone Decanoate: Nandrolone decanoate (Deca-Durabolin) is 19nortestosterone with the addition of a 10-carbon decanoate
ester added to the 17-b hydroxyl group. This addition extends
the half-life of the drug considerably. Nandrolone is
apparently a potent anabolic drug with a relatively favorable
safety profile at therapeutic dosages. It is reduced by 5-a
reductase in target tissues to the less potent androgen,
dihydronandrolone. Nandrolone appears to possess a low
affinity for aromatization to estrogen (501). Nandrolone and
its esters (decanoate and phenylpropionate) differ only in
their half-lives due to the difference in ester properties.
Nandrolone decanoate is an injectable preparation and lacks
the hepatotoxic C-17 group. It is one of the most widely
abused drugs due to its efficacy, safety profile, and worldwide
manufacture.
Ethylestrenol. Ethylestrenol (Maxibolin, Orabolin) is an
oral 19-nortestosterone derivative and was marketed in the
U.S.A., but it has since been discontinued. It differs from
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nandrolone by the addition of a 17-a-ethyl group to reduce
first-pass metabolism as well as the deletion of the 3-keto
group. This latter omission seems to reduce AR binding. This
drug appears to possess very little anabolic or androgenic
effect at therapeutic doses.
Trenbolone. Trenbolone is a derivative of nandrolone with
several additions. First, the addition of a cis-9 to cis-10 double
bond supposedly inhibits aromatization, and a cis-11 to cis-12
double bond is considered to greatly enhance AR binding.
This drug appears to possess potent androgenic and anabolic
characteristics. It is comparably more androgenic than
nandrolone due to its lack of conversion to a weaker
androgen by 5-a reductase. Trenbolone is a European drug
with a very high abuse record. In the U.S.A., it is used in
veterinary preparations as trenbolone acetate.
Common Dihydrotestosterone Derivatives. Oxandrolone: Oxandrolone (Anavar) is a derivative of DHT, and because it is
C-17 methylated, it is an oral preparation. The second carbon
substitution with oxygen is thought to increase the stability of
the 3-keto group and greatly increase its anabolic component.
This drug is considered to be very anabolic with little
androgenic effect at therapeutic doses. 5-a reductase does not
appear to reduce oxandrolone to a more potent androgen,
and because it is a DHT derivative, it cannot be aromatized.
Oxandrolone is one of a few agents to be routinely abused
by female athletes due to its mild androgenic properties.
Athletes such as weightlifters, boxers, and sprinters use
oxandrolone seeking to increase strength without additional
weight gain.
Stanozolol. Stanozolol (Winstrol) is a drug with supposed
anabolic and androgenic characteristics due to the stability
afforded by the 3,2 pyrazol group on the first cyclohexane
ring, which apparently greatly enhances AR binding. This
drug can be C-17 methylated, thus making it an oral
preparation; however, it also can be prepared as an injectable
without C-17 methylation. Stanozolol appears to be active in
both androgen- and anabolic-sensitive tissues. It is a weaker
androgen than DHT that appears to exert comparatively less
androgenic effect. As a result, it does not appear to aromatize
to estrogenic metabolites.
Oxymetholone. Oxymetholone (Anadrol) is an oral drug
because it is C-17 methylated. The 3-keto stability added by
the 2-hydroxymethylene group supposedly enhances the
drug’s anabolic properties. The action of this agent in
androgen-sensitive tissues is much like that of DHT;
therefore, it quite androgenic. Oxymetholone is the only
anabolic-androgenic steroid to date to be considered
a carcinogen (466). This drug does not appear to be
susceptible to aromatization. However, it is thought to
activate estrogen receptors via the 2-hydroxymethylene
group, thereby exerting many estrogenic side effects. In
addition, because of the drug’s C-17 methylation, it is
considered to be hepatotoxic.
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Designer Androgens. Indeed, an emerging clandestine industry
has allowed athletes to evade detection via the use of novel
‘‘designer androgens.’’ Several test-evading designer androgens have been identified in the past 3 years including a
compound known as desoxymethyltestosterone, also
known as Madol, that was never marketed (445) and a novel
chemical entity that was specifically synthesized to evade
detection (tetrahydrogestrinone, THG) (105). Desoxymethyltestosterone possesses the characteristics of a selective
androgen receptor modulator (SARM) and displays potent
anabolic effects (147). Tetrahydrogestrinone, implicated in
the Bay Area Laboratory Cooperative (BALCO) investigation, was never marketed and apparently developed as a
potent androgen that was undetectable by conventional
International Olympic Committee (IOC)–mandated urinary
sports doping tests. Tetrahydrogestrinone is a potent
androgen and progestin that binds with high, but unselective,
affinity to the AR and is able to transactivate AR-dependent
reporter gene expression. However, this level of expression is
2 orders of magnitude lower compared with DHT (195).
Relative to designer androgens, their distribution for use
at high doses without any prior biological or toxicological
evaluation poses significant health risks. Although this diversion of science may highlight the possibility of tissue-specific
effects highlighting the beneficial effects of androgens, the
potential for undesirable effects may go unnoticed. As such,
further developments require better understanding of the
post-receptor tissue selectivity of designer androgens, comparable to the mechanism underlying that of selective
estrogen receptor modulators (SERMs).
Selective Androgen Receptor Modulators. Testosterone and their
synthetic derivatives, which are known to produce significant
side effects (discussed in more detail later), spurred the
development of SARMs. These synthetic ligands were
designed to produce selective tissue-specific anabolic actions
in muscle and bone, with minimal androgenic actions in other
peripheral tissues. Selective androgen receptor modulators
were first reported in 1998, and currently, several classes of
SARMs exist including quinolines, tricyclics, bridged tricyclics, bicyclics, aryl propionamides, and tetrahydroquinolines
(381,442). These ligands bind to the AR with high affinity,
thereby strengthening the anabolic properties, yet are not
subject to aromatase or 5a-reductase activity so their
androgenic properties are low (381,442). In addition, they
have favorable pharmacokinetic properties and great potential for biochemical modifications indicative of a more
favorable alternative to anabolic steroids and related
compounds for therapeutic interventions (442).
History of Androgen Use
The interest in improving physical performance appears to
have occurred as an offshoot of early research, which sought
to determine the physiological and performance effects of
testicular extracts (194). As early as 1849, scientists had
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suggested that a substance secreted by the testes into the
blood stream was related to physiological and behavioral
characteristics of male animals (194). In 1889, BrownSéquard, considered by many as one of the founding fathers
of modern endocrinology, published results from his autoexperimentations on testicular substances in which he
reported increases in muscular strength, mental abilities,
and appetite (156,194). Although the results of his work were
never substantiated, it did give rise to the new field of
organotherapy in which testicular extracts were injected or
testicles were transplanted into patients with various
disorders (194). By the end of 1889, some 12,000 physicians
were administering Brown- Séquard’s testicular extracts as
the new ‘‘elixir of life’’ (227,494).
Largely based on Brown-Séquard’s work, Zoth and Pregl
began to investigate the effects of injections of testicular
extracts on muscle strength and athletic performance
(156,244). Zoth and Pregl injected themselves with extracts
from bull testicles and measured strength of their middle
fingers and recorded fatigue curves during a series of
exercises. In 1896, Zoth published an article suggesting that
injections of testicular extracts improved muscular strength
and the ‘‘neuromuscular apparatus’’ (156,244). Although it is
likely that these results were placebo effects, Zoth may be the
first person to suggest injecting athletes with hormones in an
attempt to increase performance (243,244).
Not until 1929 was the first sex hormone isolated
(156,243,244). In 1929, Butenandt was the first to isolate
the sex hormone estrone from the urine of pregnant women
and later was credited with isolating 15 mg of androsterone
(‘‘andro’’ = male, ‘‘ster’’ = sterol, ‘‘one’’ = ketone) from the
urine of local policemen (156). Ultimately, comparisons
were made between sex hormones isolated from urine and
those isolated from the testes. These comparisons revealed
that the hormones isolated from the testes had greater
androgenic properties than those extracted from the urine
(244). Once sex hormones were isolated, a new path of
scientific discovery was initiated.
In the 1930s, pharmaceutical companies were very interested in isolating the testicular hormone, which in 1935 was
termed testosterone (‘‘testo’’ = testes, ‘‘ster’’ = sterol, ‘‘one’’=
ketone) by Kàroly David and his research team (130,156).
During the 1930s, there was a great interest in synthesizing
artificial testosterone, and in 1935, Butenandt and Hanish
published the first paper documenting the synthesis of
testosterone from cholesterol (130,156). Only 1 week later
Ruzicja and Wettstein also published a paper that outlined
another method for the synthesis of artificial testosterone
(429). Around this time, Kochakin reported that androgens
could stimulate protein anabolism and stimulate growth. It
was further speculated that androgen therapies may be
effective in stimulating growth and restoring tissue in subjects
with a variety of disorders (156,245). Shortly after its synthesis,
oral and injectable testosterone preparations became available
to the medical community (544).
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Much of the early research looking at human use of
testosterone was conducted in Germany before World War II
(500). In fact, some have speculated that German athletes
may have been given testosterone in preparation for the 1936
Olympics (544). Additionally, it has been suggested that
German soldiers were given testosterone to increase aggressiveness in battle during this time frame (519). However, to
date, no data have been discovered to substantiate the use of
testosterone by either German athletes or soldiers during this
period (544).
Clinical trials designed to explore the effect of exogenous
testosterone use on humans were underway as early as 1937
(244). This early work involved the injection of testosterone
propionate and the oral consumption of methyltestosterone
(156,244). Ultimately, the early testosterone studies explored
the effects of the newly synthesized compound as a tool
for treating men with hypogonadism and impotency (244).
At this time, testosterone therapies were also used to treat
a variety of medical conditions associated with women
including menorrhagia, painful breast syndrome, dysmenorrrhea, and estrogen-driven breast cancers (244). The administration of testosterone in women during this period revealed
that the daily use of topical testosterone preparations resulted
in increased sexual desires and clitoral hypertrophy (243,244).
Although the administration of testosterone to women
consistently resulted in an increased sex drive, it did not
become a standard therapy because of the noted side effects
associated with the drug. Clinicians in this period noted that
women who were treated with testosterone preparations not
only experienced clitoral hypertrophy but also experienced
increased hair growth on the body and face and demonstrated
a deep husky voice (243,244). The occurrence of these side
effects resulted in many heated debates in the scientific
literature about the efficacy of using testosterone therapies in
women (244).
In 1939, Bjoe suggested that sex hormones might enhance
physical performance (71). During the 1940s, it was
discovered that testosterone could facilitate muscular growth
and much speculation about the performance effects of
testosterone occurred (244). This hypothesis was confirmed
in 1942 when Kearns and colleagues (286) reported that the
implantation of a testosterone pellet in a gelding coupled
with training significantly improved physical performance. It
was also speculated that the age-induced declines in working
capacity were directly related to the concomitant declines in
testosterone seen with aging. This led to further speculation
that testosterone therapies may be able to increase working
capacity as one ages (243,244).
de Kruif in his popular text ‘‘The Male Hormone’’ raised the
hopes and expectations for the use of testosterone by
suggesting that the administration of testosterone could
increase muscle mass, rejuvenate individuals, and elevate their
working capacity (135). In fact, de Kruif suggests that it would
be interesting to see what athletes who were systematically
using testosterone could do in competition (500). Several
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reports suggest that West Coast bodybuilders in the late
1940s and early 1950s began experimenting with the use of
testosterone preparations (244,544). Additionally, it appears
that the use of testosterone and its synthetic derivatives
began to infiltrate sports during the 1950s (500,544).
At the 1952 Olympic Games, the Soviet Union did
exceptionally well in the weightlifting competition, which
led to speculation that some sort of hormone manipulation was
being employed (500). This contention seems to be supported
by statistical analyses of the performance of the Soviet
weightlifters during this time frame (176). In 1954 at the World
Weightlifting Championships, Dr. John Ziegler was told by his
Soviet counterpart that the Soviet weightlifters were indeed
using testosterone (500). After the completion of the world
championships, Dr. Zeigler returned to the U.S.A. and
immediately began experimenting with testosterone use. In
his early work with testosterone he became concerned with
potential side effects, such as prostate problems and increased
libido (500). Ultimately, this led him to search for a drug that
had pronounced anabolic effects while minimizing the
androgenic effects (500).
In 1958, the first U.S. manufactured androgen Dianabol
(methandrostenalone) was approved by the U.S. Food and
Drug Administration (156,500). This new drug provided
a potential solution to the side effects noted with testosterone
use. To explore the effectiveness of Dianabol administration
in athletes, Dr. Ziegler administered the drug to 3 members of
the York Barbell Weightlifting team (500). Dianabol proved
to be a very effective drug when coupled with resistance
training, and the athletes experienced a meteoric rise in
performance (500). News of the drug’s application as an
ergogenic aid spread to other strength- and power-based
sports including the field events in track and field and
American football (544).
In 1960, the use of androgens by Olympic athletes was still
not a major problem and was probably limited to American
and Soviet strength athletes (544). By the 1964 Olympic
Games, the use of androgens became significantly more
extensive in all strength sports (500,544) and was a growing
problem (98). In 1965, oral turinabol was synthesized by
a German Democratic Republic (GDR) state–owned
pharmaceutical company (505). By 1966, the GDR began
a state-sponsored doping program designed to enhance
sports performance and prepare athletes for the 1968
Olympic Games in Mexico City (191). Interestingly, it
appears that the GDR was the first to administer the drug to
women athletes as they prepared for the 1968 Olympic
Games (191,505)
With the increasing use of performance-enhancing drugs
and several high-profile deaths of athletes from various sports,
the IOC established a medical commission in 1967. The
primary goal of the IOC Medical commission was to develop
a list of prohibited substances and methods (192). The IOC
also adopted a medical code that encompassed 3 principles:
(a) protection of the health of the athlete, (b) respect for both
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medical and sports ethics, and (c) equality for all competing
athletes (192).
By the 1968 Olympics, an incremental increase in use was
seen in track and field (544). Support for this contention can
be seen in reports that suggest that one-third of the U.S. track
and field team (i.e., throwers, sprinters, hurdlers, and middle
distance runners) had used these drugs in the lead up to the
1968 Olympic Games (500). Additionally, documentation
has been discovered that reveals that at the 1968 Olympics
many of the male and female athletes from the GDR were
systematically using various anabolic-androgenic drugs to
enhance athletic performance (191). Although androgen use
was on the rise during this time frame, there was little debate
about the ethics of taking androgens. Most discussion among
athletes centered on which drugs were most effective (544).
In 1969, androgen use was so prevalent that John
Hendershott the editor of Track & Field News called these
drugs the ‘‘breakfast of champions’’ (234). Throughout the
1960s, the overall volume of androgen use increased
dramatically. In fact, it appears that athletes increased the
dosages used to levels that were 2–5 times above the
recommended therapeutic dosage (544) and performance
gains increased (191). Additionally, athletes began preferentially taking androgens and began experimenting with
stacking drugs that included a combination of oral and
injectable forms (544). During these years, the IOC failed to
include androgens on the banned substance list. One reason
for this was that the medical community suggested that
androgens were ineffective and were unwilling to consider
that the use of these drugs could impact performance. This
was primarily based on several poorly designed studies (this
will be discussed in greater detail in the next section).
Ultimately, this caused a large credibility gap between
athletes and the medical community as many athletes
developed a large distrust for medical doctors (500). The
second reason for the exclusion of androgens was that there
simply were no reliable and valid tests at this time (500).
In 1973, the first testing procedures for androgens were
proposed. The first method used radioimmunoassay procedures, whereas the second suggested using a combination of
gas chromatography and mass spectrometry (GC-MS)
techniques. The IOC ultimately adopted both methods to
ensure the highest accuracy in testing; however, very few
laboratories in the world could conduct the test at the levels
required by the IOC. The testing protocols were first
implemented in the 1974 Commonwealth Games in Auckland, New Zealand, where 9 out of 55 samples were positive
for androgens (500).
Throughout the early 1970s, the GDR expanded its doping
program to include most sports, and it became customary to
provide drugs to most athletes including minors (191). In fact,
the overall dosages of the drugs used by athletes from the
GDR continued to escalate to the point at which damaging
side effects became apparent, especially in the female athletes
who were outwardly androgenized (191). With the advent of
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testing in 1974, the GDR faced a very unique problem in that it
was apparent that the use of androgens was a key to their
success in international competition, but the advent of drug
testing created a possible problem to the systematic program
being used. At the 1974 European Athletic Championships in
Rome, drug testing of urine samples revealed no positive steroid
tests. However, the IOC was developing new drug testing
processes that created a situation in which the GDR feared
many of its most successful athletes would test positive (191).
In 1974, the GDR government instituted a top secret
program that provided for the administration of androgens
and other doping products to male and female athletes. This
program contained 6 central concepts, which included (a) the
mandate that doping plays a central role in the training
process and preparation of athletes for major international
competition; (b) the establishment of a monitoring program
in which sports physicians conducted regular evaluations of
the athletes; (c) the development of a centralized drug
distribution and documentation program, which was under
the control of the Sportmesizinischer Dienst (SMD); (d) the
organization of a systematic research program into the
development of new doping products and the establishment
of drug administration programs, which would allow for
the avoidance of detection during doping controls; (e) the
development of a comprehensive educational program in
which coaches and physicians would be instructed about
doping; and (f ) the classification of the doping program as an
Official State Secret (191). The timing of the program was
extremely important as the IOC had planned to test at the
1976 Olympic Games and the GDR wanted to continue to
build upon its growing success in international competitions.
In 1976, drug testing was first initiated at the Olympic
Games in Montreal (500). A relatively low number of athletes
tested positive for androgens during these games (8 out of
275 tests) (500). Although it appeared few athletes were
doping based on the drug testing program instituted by the
IOC, survey data collected during the games suggested that
as many as 68% of the athletes competing had used
androgens during their training (98). It is likely that the
early drug testing programs were not as effective due to the
fact that the IOC had left off many drugs from their testing
program (500). For example, norbolethone, which was never
approved for human consumption, was reported to be taken
by several athletes but was not present on the early lists of
banned substances (98). Additionally, it has been reported
that many athletes reverted to the use of testosterone, as it
was not part of the original testing program (500).
By 1979, the GDR doping program had expanded to the
point that athletes were being given complex combinations of
drugs. For example, Franke and Berendonk (191) reported
that one GDR weightlifter was administered 11.55 g of oral
turinabol, 13 injections of testosterone esters, and human
chorionic gonadotropin (hCG). Most noted was the development of ‘‘steroid bridging,’’ which replaced readily detectable steroids with testosterone esters in the weeks before
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competition to circumvent drug testing protocols. Typically,
athletes would receive repeated intramuscular injections of
testosterone esters of various fatty acid chain lengths in the
time period leading up to a major competition (191). This
process was quite commonplace in the GDR and many other
countries. Before the 1980s, there was no method available
for the detection of testosterone use to drug testers.
In 1980, Professor Manfred Donike the head of the IOCapproved drug testing laboratory in Cologne, West Germany,
developed a method for detecting testosterone use by
comparing the testosterone to epitestosterone ratio (T:E
ratio) (500). Because the use of testosterone results in an
increase in testosterone levels without a concomitant increase in epitestosterone, athletes who possessed a T:E ratio
of 6:1 were suggested to be doping. After the 1980 Olympic
Games in Moscow, the T:E ratio was determined and it
was detected that ;20% of all athletes tested had a T:E ratio
of .6:1 (29) and 7.1% of female athletes tested had a T:E
ratio of .6:1 (191). After the development of the T:E ratio
test, the IOC implemented the protocol as part of its
doping controls.
The advent of the T:E ratio test caused significant problems
for the state-instituted doping program of the GDR. In a 1981
meeting in the GDR, it was determined that a program to find
alternatives to exogenous testosterone administration was
needed and that testosterone was to be replaced by its
precursors (i.e., androstenedione, DHT, dihydroanodrostenedione, or DHEA) (191). By 1982, scientists from the GDR
had determined that 3 days after the injection of 25 mg of
testosterone propionate, the T:E ratio would be below the
6:1 cutoff used by drug testers. Additionally, it was discovered
that hCG and clomiphene did not alter the T:E ratio (191).
By 1983, the GDR had determined a method for
simultaneously injecting testosterone and epitestosterone,
which consistently kept the T:E ratio below the 6:1 cutoff.
With this information in hand, the GDR had a method that
allowed them to circumvent doping controls.
The T:E ratio test was first administered at the 1983 Pan
American Games in Caracas, Venezuela, where a total of 15
athletes tested positive (11 weightlifters, 1 cyclist, 1 fencer,
1 sprinter, and 1 shot putter) (500). There may have been
more positive tests but 12 American athletes chose to leave
the games before competing and thus avoided being tested.
Journalists and commentators seemed shocked by the
apparent doping problems that were brought to light by
the Pan American Games in Caracas (500). At this time,
journalists began reporting that androgens were not only
a part of Olympic sports such as weightlifting but were
also a part of every other professional sport in America. More
disturbing was the fact that collegiate (e.g., National
Collegiate Athletic Association [NCAA]) and professional
sport (e.g., NFL, MLB, NBA, and NHL) organizations, and
even professional bodybuilding, were doing nothing to curb
the use of androgens (500). For example, it has been speculated that between 50 and 75% of offensive and defensive
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linemen in the NFL used steroids during the 1980s, but the
precise level of use will probably never be known (544).
Although the T:E ratio test was implemented at the 1984
Olympic Games in Los Angeles, the most famous androgen
positive occurred at the 1988 Seoul Olympic Games when
Canadian sprinter and then current world’s fastest man Ben
Johnson tested positive for stanozonol (98). This positive test
sent shock waves through the sporting community, ultimately resulting in the U.S. government passing the AntiDrug Abuse Act, which made it illegal to distribute or possess
androgens (98). Additionally, the IOC expanded the banned
substance list to include diuretics, such as probenecid, and
other products typically used to mask androgens use (315). In
1990, the U.S. government went a step farther when it passed
the first Anabolic Steroid Control Act and inserted 27
steroids, along with their muscle building salts, esters, and
isomers as class III drugs and simple possession could result
in prison time (117)
As drug testing became more developed, the interest in the
use of dietary supplements as performance enhancement
tools increased. In 1994, the U.S. government passed the
Dietary Supplement Health and Education Act (DSHEA),
which was designed to protect the consumer from the risks of
taking certain substances. For example, the Food and Drug
Administration used this act to ban ephedra (117). In 1996,
the prohormone androstenedione, which was first used by
the GDR in 1981, was introduced to the American market as
a new dietary ingredient (117). Because it was classified as
a new dietary ingredient, it was not subject to regulation by
the DSHEA (117). In fact, androstenedione became a very
popular dietary supplement when Mark McGwire admitted
to using it in 1998 (116).
In 1999, the IOC took an unprecedented step and convened
the World Conference on Doping in Sport in Lausanne,
Switzerland. Ultimately, this conference served as the
foundation for the formation of an international anti-doping
initiative, which resulted in the formation of the World AntiDoping Agency (WADA) in 2001 (192). By 2002, WADA had
developed the world anti-doping code, which contained
3 major parts: (a) the code, (b) international standards, and
(c) models of best practice (192). The international standards
serve as the operational and technical areas that are
contained within the anti-doping program and integrate
anti-doping agencies with the overall anti-doping code. The
anti-doping code contains international standards for (a)
laboratories, (b) testing procedures, (c) substances contained
on prohibited lists, and (d) mechanisms and rules for
therapeutic exemptions (192). As a whole, WADA oversees
doping controls for international competitions including the
Olympic Games and world championships as well as other
sporting events that fall under the IOC (192). These doping
controls are not only performed at competitions but are also
performed as no-notice out-of-competition controls. In this
capacity, WADA requires athletes to report their whereabouts so that random drug testing can be conducted. If the
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athlete either fails a doping control test or fails to show for
testing WADA has the power to sanction athletes, which
ultimately can withhold them from competition indefinitely
depending upon the number of doping offenses the athlete
has. Since 2000, WADA has performed out-of-competition
testing for sports, which are encompassed under the IOC
governance. However, to date, professional sports in America
have yet to allow WADA to perform in or out-of-competition
testing in their sports, and it is unlikely that they ever will.
In 2003, a syringe containing an unknown compound was
sent to the U.S. Anti-Doping Agency that would expose
a doping program that could only be compared with
the program once run by the GDR (105,296). Eventually,
the compound in the syringe was isolated and determined to
be THG, which was at the time a new undetectable steroid
(105,296,298). After its isolation, the drug source was linked
to the BALCO, and the subsequent scandal associated with
this drug exposed a widespread doping problem in American
sports (298). By 2004, a second designer steroid known as
Madol was isolated by the UCLA laboratory (445). The
discovery of these designer steroid compounds suggests that
unscrupulous athletes and scientists are still trying to
circumvent the drug testing controls, much like the GDR
did in the 1980s.
In 2004, the U.S. Senate held hearings on the abuse of
androgens and their precursors by athletes. By the end of
2004, a new Anabolic Steroid Control act was implemented,
which contained 26 new steroid compounds, including many
of the steroid precursors such as androstenedione and
androstenediol. Additionally, designer steroids such as
THG were also added to the controlled substances listed
by the act (117).
Another change in the world of doping controls occurred in
2005 when WADA lowered the T:E ratio, which indicated an
adverse analytical finding from 6:1 to 4:1 (536). If the athlete
were to test positive for an elevated T:E ratio (.4:1), then
a follow-up test consisting of the use of an isotope ratio mass
spectrometry (IRMS) procedure was to be used (536).
Ultimately, the IRMS test was suggested to be an accurate
way to determine if synthetic doping products were taken by
the athlete (1). The advent of these new testing procedures
would result in some interesting doping findings in 2006
(further discussion on testing for androgens will be presented
later in this report).
In 2006, the sporting world was yet again rocked by another
doping scandal. Before the 2006 Tour de France, the Spanish
Civil Guard began investigating Dr. Eufemiano Fuentes for
providing doping products to cyclists and athletes from other
sports (328). The investigation resulted in several high-level
cyclists being excluded from the Tour de France in 2006 and
some were subsequently sanctioned. At the end of the 2006
Tour de France, it was revealed that the winner American
Floyd Landis tested positive for an abnormal T:E ratio and as
of 2008 he has been stripped of his title under the suspicion of
using testosterone (168). Up to this point, it was widely
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believed that androgens use was limited to strength and
power athletes. However, evidence from this race revealed
that androgen use was now prevalent in endurancebased sports as well.
In 2007, Marion Jones admitted to taking banned drugs
including THG during the 2000 Olympic Games in Sydney,
Australia (410). What is unique about the Marion Jones case
is that she was proven guilty of doping without ever testing
positive for performance-enhancing substances. She was
initially linked to the BALCO scandal in 2004 and repeatedly
denied using anabolic steroids, but in 2007, she admitted to
using performance-enhancing drugs before and during the
2000 Olympic Games. By the end of 2007, an independent
report on androgen use in professional baseball was released,
which suggested that the use of androgens and other
performance-enhancing drugs is a serious problem in
professional baseball in the U.S.A. (360). Table 3 provides
a time line of the history of androgen use.
Research on Androgens as a Performance-Enhancing Drug
Studies investigating the performance-enhancing effects of
androgen administration have yielded conflicting findings.
Although athletes were making significant gains with androgen
use since the mid-1950s (with a possibility athletes may have
began to experiment with androgens prior to this period of
time), early research did not corroborate the anabolic and
ergogenic effects experienced by athletes. Thus, academia
decried their efficacy citing a lack of evidence. In fact, the ACSM
between 1976 and 1984 regarded androgens as being ineffective
until they revised their position in 1984 (9,10). Several important
factors must be considered when interpreting results of these
studies. For example, some early studies that have shown
limited effects were plagued by poor scientific design (i.e.,
nonrandomized, not double-blind, no-placebo trials used) and
issues that contrasted with how athletes were using androgens
in real-world settings. In these studies, researchers oftentimes
administered too low a dose of androgens (e.g., a clinical dose
or lower typically prescribed for androgen deficiency, which is
far exceeded by athletes), and this study did not have subjects
train in conjunction with androgen use (e.g., whereas athletes
were training at a high level), did not examine ‘‘stacking’’ of
androgens or the compounding effects of multiple-drug use
(e.g., most androgen users stack multiple drugs), used untrained
subjects (which undergo an extend neural phases initially that
may mask potential increases from androgens), and failed to
examine dietary interventions such as increased protein intake
coinciding with androgen use (e.g., many androgen users
increase protein and kilocalories consumption greatly). This
information notwithstanding, androgen research before 1980
was inconsistent regarding its efficacy.
Androgen Studies Before 1980. An early performance study was
performed by Samuels and colleagues (434) who reported
that 50 mgd21 of methyltestosterone (plus 250 mg of
creatine hydrate) for 3 weeks did not enhance grip strength in
untrained subjects. Nearly a quarter of a century had passed
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before androgen ergogenicity studies resurfaced with greater
frequency predominantly in non–resistance-trained subjects.
Several studies did not report ergogenic effects of anabolic
steroids on muscle strength or performance. Fowler et al.
(190) administered 20 mgd21 of methenolone acetate
(Nibal) for 16 weeks to untrained subjects who either did
not exercise or exercised 30 mind21, 5 dwk21 and reported
that androgen use did not enhance muscle size, body weight,
or isometric strength. Weiss and Muller (527) also did not
report any greater enhancement of grip strength or body
weight after administration of 10 mg of Dianabol for 17 days
in high school students. Casner et al. (104) administered
6 mgd21 of Winstrol in some subjects’ weight training
3 dwk21 and reported no ergogenic effects of androgens on
isometric strength, although body weight gains were greater
in the androgen/lifting group. Fahey and Brown (174)
administered 1 mgkg21 body mass of Deca-Durabolin every
second or third week for 9 weeks in college students’ weight
training 3 dwk21 (3–5 sets of 1–5 repetitions) and reported
statistically similar increases in strength compared with
a control group (13–15 kg compared with 6–10 kg). Stromme
et al. (486) administered 75 mgd21 of mesterolone
(Mestoranum) for 4 weeks and 150 mgd21 for the
subsequent 4-week period in college students taking a weight
training class and reported similar increases in isometric
strength to a control group. Hervey and colleagues (237,238)
administered 100 mg of Dianabol (or placebo) for 6 weeks in
a crossover design and reported greater gains in body weight
and girth measurements with androgen use, but no
significant difference was observed in lifting performance
between androgen and placebo conditions. Loughton and
Ruhling (329) administered 10 mgd21 of Dianabol for 3
weeks and 5 mgd21 for 3 more weeks concomitant with
weight training and running program and reported greater
weight gains in the androgen group but nonsignificant
interactions in strength performance.
Several early studies in lesser trained individuals did show
ergogenic potential of androgens. Johnson and O’Shea (273)
weight trained subjects for 6 weeks but administered 10 mg
of Dianabol (plus protein) daily the last 3 weeks to half of the
subjects and reported significantly greater gains in isometric
strength and 1 repetition maximum (1RM) squat (although
other strength measures did not reach statistical significance)
in the steroid group. In a follow-up study, Johnson et al. (272)
reported similar findings where androgens enhanced muscle
strength and girth to a greater extent. Win-May and Mya-Tu
(533) administered 5 mgd21 of Dianabol to university
students over 3 months (little was known about their physical
activity) and reported greater gains in grip strength, push-up,
and pull-up performance in the steroid group.
Most early studies examining androgen use in trained
subjects demonstrated ergogenic potential in muscular
strength and performance. O’Shea and Winkler (379)
administered 10 mgd21 of Anavar (plus protein) to
swimmers and weightlifters for 6 weeks and reported large
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TABLE 3. Time line of major events related to androgen use.*
Year
1889
1896
1928
1929
1935
1935
1935
1935
1937
1938
1939
1939
1942
1944
1945
1952
1954
1958
1959
1960
1960
1962
1964
1965
1966
1967
1967
1967
Author
Brown-Séquard Presents data on autoexperimentation of the injection of testicular extracts.
Suggests improvements in muscular strength occur.
Zoth and Pregl Investigated the effects of testicular extracts on muscle strength and athletic
performance and were the first individuals to suggest injecting athletes with
hormones.
The International Amateur Athletics Federation (IAAF) becomes the first sports
federation to ban the use of doping products (i.e., stimulants)
Butenandt
Isolated the esterone from the urine of pregnant women and later androsterone
from urine of local policemen.
David et al.
Isolated the testicular hormone known as testosterone.
Butenandt and Published first paper on the synthesis of testosterone from cholesterol.
Hanish
Ruzicja and
Published second paper on the synthesis of testosterone.
Wettstein
Kochakin
Reported testosterone stimulates protein anabolism and stimulates growth.
Suggested that testosterone therapies may be useful for several disorders.
Clinical trials looking at testosterone conducted.
Androstenedione synthesized.
Testosterone administered to women for a variety of medical conditions is begun.
Noted effects are increases in sex drive and clitoral hypertrophy. Side effects
such as a deeper voice and the increase growth of facial and body hair are
also noted.
Boje
Suggests sex hormones may enhance physical performance.
Kearns et al.
Report that administration of testosterone improved performance of a gelding trotter.
Speculation that reductions in work capacity with age are related to age-induced
declines in testosterone.
de Kruif
Published the book The Male Hormone in which he touts the use of testosterone
for increasing muscle mass and increasing work capacity. Suggests it would
be interesting to see what athletes who were systematically using testosterone
could do in competition.
Hoffman
Bob Hoffman of York Barbell speculates that the Soviets have used hormones to
elevate performance during the Olympic Games.
Zeigler
Zeigler told by Soviet team physician that Soviet Weightlifters were using
testosterone.
Ciba Pharmaceutical Company releases Dianabol
Zeigler
Once dianabol (methandrostenolone) was synthesized began testing it on
members of the York Barbell Weightlifting Team.
Speculation that anabolic-androgenic steroid use is limited to Soviet and
American weightlifters
Death of a Danish cyclist at the 1960 Olympics puts pressure on sports authorities
to deter doping (amphetamine use)
The Council of Europe published an initial list of banned substances including
narcotics, amine stimulants, alkaloids, respiratory tonics, and certain hormones.
Anabolic-androgenic steroid use increases to include most strength power athletes.
Oral turinabol was synthesized by VEB Jenapharm, a German Democratic
Republic State owned pharmaceutical company.
The German Democratic Republic begins a systematic program to investigate
and administer illegal drugs including anabolic-androgenic steroid to athletes.
First documented systematic program to administer anabolic-androgenic
steroids to women.
British cyclist died during the Tour de France as a result of amphetamine use.
International Olympic Committee establishes a medical commission and
banned drugs.
International Olympic Committee adopts a medical code which encompassed
3 principles: (a) protection of the health of the athlete, (b) respect for both
medical and sports ethics, and (c) equality for all competing athletes.
(Continued on next page)
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1968
1968
1969
Hendershott
1973
1974
1974
1975
1976
1980
1980
1981
1982
1982
1983
1983
1984
1988
1988
1988
1990
1994
1996
1998
1998
1999
2001
2001–2002
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the
Anabolic-androgenic steroid use increases. Estimated that one-third of the
U.S. track and field team used the drug in the 1968 Olympics. Most athletes
from the German Democratic Republic were systematically using
anabolic-androgenic steroids.
Drug testing was conducted for research purposes at the 1968 Winter Olympic
Games in Gernoble, France, and the Olympic Summer Games in Mexico City,
Mexico. Anabolic-androgenic steroids were not tested for, as they were not
banned at this time.
The editor of Track & Field News called anabolic-androgenic steroids the
breakfast of champions.
Radioimmunoassay and a combination of gas chromatography and mass
spectrometry suggested as possible test for anabolic-androgenic steroids.
To ensure accuracy, both testing procedures were adopted by the
International Olympic Committee.
First anabolic-androgenic steroid testing conducted at the Commonwealth
Games in Auckland, New Zealand. No sanctions were administered,
despite 9 of 55 samples contained anabolic-androgenic steroids.
The German Democratic Republic institutes a Top Secret program to systematically
dope athletes and circumvent IOC instituted drug testing
First sanctions for positive anabolic-androgenic steroid drug test handed out to
2 track athletes competing at the European Cup.
Drug testing was instituted at the 1976 Olympic Games. Eight athletes out of
275 tested were found to be positive for anabolic-androgenic steroids
(7 weightlifters and 1 discus thrower). Two of the weightlifters were Americans,
Mark Cameron and Phil Grippaldi.
Dr. Donike developed test for testosterone, 6:1 testosterone to epitestosterone
ratio established as a screening tool for doping.
Testing of unused urine samples from the 1980 Moscow Olympic Games revealed
that 20% of all athletes had T:E ratios greater than 6:1 and 7.1% of all female
athlete samples were above the 6:1 ratio.
GDR decided to replace testosterone administration with androstenedione,
various forms of dihydrotestosterone, dihydroandrostenedion, or
dehydroepiandrosterone
Testing for testosterone was introduced for the 1984 Olympic Games by
the IOC, the T:E ratio is set at .6:1.
GDR begins the administration of hCG, Clomiphen that did not affect T:E ratio.
Additionally, the GDR discovers that 3 days after the injection of testosterone
propionate, the T:E ratio was below 6:1.
The GDR discovers the dosage of epitestosterone needed to keep the T:E ratio
below 6:1 when exogenous testosterone was used.
Testosterone screening is first conducted at the 1983 Pan American Games in
Caracas Venezuela. Fifteen athletes were caught for doping: 11 weightlifters
(some were using testosterone), 1 cyclist, 1 fencer, 1 sprinter, and 1 shot putter.
First use of the T:E ratio test at the Olympic Games in Los Angeles.
Ben Johnson tested positive for Stanozolol at the 1988 Olympic Games
Testing for diuretics and other masking agents for anabolic-androgenic steroids begins.
The U.S. government passed the Anti-Drug Abuse Act, making the distribution or
possession of anabolic-androgenic steroids for nonmedical reasons a
federal offense.
The U.S. government passed the first Anabolic Steroid Control Act and inserted
27 steroids, along with their muscle building salts, esters, and isomers as
class III drugs and simple possession could result in jail time.
The U.S. Congress passed the Dietary Supplement Health and Education Act.
Androstenedione was first marketed as a dietary supplement in the U.S.A.
Mark McGwire admitted using androstenedione; consequently, sales of the
dietary supplement increase incrementally.
A large number of prohibited medical substances were found during drug raids
conducted at the Tour de France.
The first World Conference on Doping in Sport was held in Lausanne, Switzerland.
The World Anti-Doping Agency was formed.
The world anti-doping code was developed by the World Anti-Doping Agency.
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2002
2002
2003
2003
2004
2004
2004
2004
2005
2006
2006
2007
2007
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The first known designer steroid Norbolethone was isolated by the UCLA Olympic
Analytical Laboratory.
American Track Cyclist Tammy Thomas banned for life for taking Norbolethone.
Syringe sent to USADA with unknown substance. Later determined to be
designer steroid known as tetrahydrogestrinone.
Bay Area Laboratory Cooperative Scandal Revealed linking many athletes to doping
The second known designer steroid Madol was isolated.
U.S. Senate holds Hearing on Anabolic-Androgenic Steroids and their precursors
by athletes.
The Anabolic Steroid Control Act is revised to include 26 new compounds including
many of the steroid precursors that to this point were commonly sold as dietary
supplements.
IOC opens investigation into Marion Jones who was linked to the BALCO scandal.
T:E ratio for a positive doping test is lowered to 4:1 by WADA. A T:E ratio of .4:1
is indicated as an adverse analytical finding and isotope mass spectrometry is
then used to determine the presence of synthetic testosterone.
The Spanish Civil Guard investigated Dr. Eufemiano Fuentes for running a doping ring.
The doping scandal linked to athletes in cycling and a variety of sports.
Floyd Landis tested positive during the Tour de France for an abnormal T:E ratio.
Marion Jones admitted to doping during the 2000 Olympic Games and was
subsequently stripped of her medals and records.
Mitchell Report on Steroid Use in Professional Baseball is released.
*GDA = German Democratic Republic; IOC = International Olympic Committee; USADA = U.S. Anti-Doping Agency;
WADA = World Anti-Doping Agency.
improvements in strength, although no control group was
used for comparison. O’Shea (377) administered 10 mgd21
of Dianabol for 4 weeks to weightlifters (half consumed
anabolic steroids, half consumed a placebo) and reported
greater strength gains in bench press in the steroid group (but
30% greater increase in squat strength in the steroid group
was not significant). Bowers and Reardon (78) administered
10 mgd21 of Dianabol (plus 30 g of protein per day) to
resistance-trained men for 3 weeks and reported greater
strength increases in the steroid group. Ariel (20) administered 10 mgd21 of Dianabol for 4 weeks to resistance-trained
varsity athletes and reported that rate of strength gains was
greater with steroid use than with placebo. In 2 other studies,
Ariel (21,22) administered 15 mgd21 of Dianabol for 4 weeks
in a crossover design and reported greater strength gains with
androgen use. Interestingly, subjects who consumed a placebo first made greater gains than subjects who consumed
a placebo the last 4 weeks, indicating that strength gains were
attenuated when androgens were discontinued. In the second
study, Ariel (22) reported that strength gains from androgen
use did not deteriorate as fast as gains made during placebo
consumption in subjects following a protocol similar to that
followed in the previous study over a subsequent 15-week
period of detraining. Ward (524) administered 10 mgd21 of
Dianabol (or placebo) for 4 weeks to weight-trained college
men during training (3 dwk21, 4 sets of 5 repetitions) and
reported significantly greater gains in bench press and squat
strength in the androgen group than in group receiving
placebo. Stamford and Moffatt (473) administered 20 mgd21
of Dianabol (plus 30 g of protein) for 4 weeks in resistance-
trained men and reported accelerated strength gains in the
androgen group compared with placebo. O’Shea (378)
administered 8 mgd21 of Winstrol (plus 0.5 gkg21 of
protein) to weight-trained men (1–2 years of experience) for
5 weeks and reported that only the androgen group increased
maximal bench press and squat strength. Freed et al. (193)
administered 10 or 25 mgd21 of Dianabol to trained lifters
for 6 weeks and reported greater strength improvements in
the androgen groups but no dose-response relationship was
found. However, Golding et al. (207) administered 10 mgd21
of Dianabol (3 weeks on, 1 off ) for 12 weeks to trained lifters
and reported no significant greater strength gains in the
androgen group compared with placebo. Thus, most of these
studies have shown greater strength and performance gains
in trained lifters using androgens compared with a placebo.
Androgen Studies: 1980–1990. Considerably less research was
conducted investigating ergogenic effects of androgens
during this time. However, study designs improved and
in some cases were more realistic. Hervey et al. (239)
administered 100 mgd21 of Dianabol (or placebo) to
resistance-trained individuals for 6 weeks in a crossover
design and reported significant increases in lower- and
upper-body strength (but not grip strength) in the androgen
group, with no changes during control (placebo) training
period. In addition, the androgen group increased body
weight and muscle circumferences to a greater extent. These
differences were quite substantial between steroid and placebo
conditions. It is important to note that in a randomized,
crossover design, those who consumed Dianabol initially had
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difficulty improving in a subsequent placebo condition. Crist
et al. (126) administered testosterone cypionate or nandrolone decanoate (100 mgwk21) or placebo to strength-trained
men for 3 weeks (plus supplemental protein) and reported
nonsignificant differences in peak isokinetic torque and lean
body mass. Although subjects in this study reported feelings
of greater strength, isokinetic testing did not reveal significant
differences. Alen et al. (4,5) examined elite power athletes
self-administering anabolic steroids (;31.0 6 14.3 mgd21 of
methanedienone, stanozolol, and nandrolone, and 178.4 6
82.7 mgwk21 of testosterone) for 24 weeks and reported
greater increases in muscle fiber area, fat-free mass (FFM),
maximal isometric force, and squat strength with androgen
use. The increases continued for 6 weeks after the
experimental period where no drugs were consumed in the
steroid group. In a case study, Häkkinen and Alen (223)
reported similar findings where an elite bodybuilder increased FFM, muscle force, and fiber area substantially
during a 6-month polydrug regimen and heavy training.
Anabolic Steroid Studies: 1990 to Present. Some studies further
examined androgen use in athletes (76). These studies
continued to report that cross-sectionally, androgen users
had greater strength and muscle mass than nonusers (76),
and longitudinally, androgens increased lean body mass,
muscle strength, and performance (63,196,203,309). However, a large increase in the number of investigations
examining the clinical use of androgens with resistance
training occurred during this period, for example, in
hypogonadal men, elderly men, and diseased populations.
In the U.S.A., most institutional review boards regarded the
administration of androgens in nonclinical settings as unethical. Thus, the number of clinical studies rose dramatically
while most studies investigating athletic ramifications were
performed outside of the U.S.A.
Friedl et al. (196) examined androgen administration of (a)
100 or 300 mgwk21 of testosterone enanthate or (b) 100 or
300 mgwk21 of nandrolone for 6 weeks in physically active
men. They reported dose-response relationships where the
largest gains in body weight and isokinetic muscle strength
were seen in most cases with 300 mgwk21 of testosterone
enanthate. Smaller increases in strength were observed with
nandrolone administration, although some did not reach
statistical significance. Bhasin et al. (63) administered a high
dose (600 mgwk21) of testosterone enanthate to weighttrained men concomitant with resistance training and
reported that the combination of androgen administration
plus resistance training produced the largest increases in lean
body mass and muscle strength than training with a placebo
or just androgen administration alone with no resistance
training. Maximum squat and bench press strength increased
38 and 22%, respectively, in the combination group compared
with ;20 and 10% increases in the group receiving placebo
plus resistance training and group administered androgen
only. Bhasin et al. (67), Sinha-Hikim et al. (460), and Storer
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et al. (482) administered 25, 50, 125, 300, or 600 mgwk21 of
testosterone enanthate (with no resistance training) to
resistance-trained men over 20 weeks and reported that
increases in lean body mass, type I and II muscle fiber area, and
thigh muscle volume were greatest at higher doses, for
example, at least 125 mgwk21. A positive relationship was
seen between lean body mass increases and dose of androgen
administered. In addition, muscle strength increased mostly
when 50, 300, and 600 mgwk21 of testosterone enanthate
were administered and androgen dose was significantly related
to changes in leg press strength. In a follow-up study,
Woodhouse et al. (535) reported that changes in muscle size
were strongly related to androgen dose. Androgen dose was
the best predictor of the anabolic response accounting for
61–65% of the variance in the anabolic response. Kuipers et al.
(309) administered 200 mgwk21 (week 1) and 100 mgwk21
of nandrolone decanoate (or placebo) to bodybuilders for 8
weeks (along with training) and reported that muscle fiber area
increased substantially only in the bodybuilders using steroids.
Hartgens et al. (230) also showed a dose-response relationship
where they reported that a supraclinical stack of androgens
increased deltoid muscle fiber area by 12.6%, whereas
administration of a more therapeutic dose (200 mgd21 of
nandrolone decanoate) did not increase fiber area in strengthtrained athletes. In a series of studies Hartgens et al. (229),
Kuipers et al. (310), and Van Marken Lichtenbelt et al. (512)
demonstrated that administration of 100–200 mgwk21 of
nandrolone decanoate for 8 weeks to bodybuilders significantly increased lean tissue mass more than a placebo. Forbes
et al. (188) administered ;42 mgkg21 body mass of
testosterone enanthate for 12 weeks in untrained men and
reported a large increase in lean body mass. Kouri et al. (304)
reported steroid users to have greater body weight and muscle
mass. Interestingly, they developed an equation to attempt
to predict steroid use based on FFM index. They reported
that androgen users had a larger FFM index (e.g., . 25.0).
Giorgi et al. (203) administered 3.5 mgkg21 body mass of
testosterone enanthate (or placebo) concomitant to 12 weeks
of periodized resistance training and reported greater increases
in body weight and bench press strength (22 vs. 9%) in the
testosterone group. Much of the gains were lost during
a subsequent 12-week period where androgens were not
administered. Using a similar administration protocol for 6
weeks, Rogerson et al. (424) reported greater increases in 1
repetition maximum (1RM) bench press strength and cycle
sprint performance in the androgen group compared with
placebo.
Several studies have investigated androgen administration
and performance in elderly (e.g., testosterone replacement),
hypogonadal men, and clinical populations. In general, these
populations tend to be very responsive as their testosterone
concentrations are low and subsequently even low-dose
testosterone replacement could have a significant impact.
Testosterone replacement has occurred mostly in the forms of
oral tablets, intramuscular injections, transdermal patches and
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gels, and buccal delivery (373). In hypogonadal young men,
several studies have shown that low-dose testosterone
replacement of 50–100 mgwk21 increased lean body mass
mostly with minimal strength augmentations (64,69). A
meta-analysis in middle-aged men showed that testosterone
replacement produced significant increases in lean body mass
(2.7%) but only sporadic increases in muscle strength (255).
In the elderly, data have been inconsistent as some studies
have shown testosterone replacement (typically low dose)
alone to increase lean body mass and muscular performance
modestly, but others have reported limited effects of
testosterone replacement (57,77,85,383). However, there
appears to be a dose-response relationship. Bhasin et al.
(68) administered 25, 50, 125, 300, or 600 mgwk21 of
testosterone enanthate to elderly men over 20 weeks and
reported that increases in lean body mass correlated to the
dose administered. In addition, muscle strength increased
mostly when at least 125 mgwk21 of testosterone enanthate
was administered, and testosterone dose was significantly
related to changes in leg press strength. Schroeder et al. (439)
administered 50 or 100 mgd21 of oxymetholone in elderly
men for 12 weeks and reported significant increases in lean
body mass and muscle strength. Although the increases in
the group receiving 100 mgd21 of oxymetholone were
greater, these data did not reach statistical significance.
Limited effects have been shown in some studies with lower
doses. Lambert et al. (314) administered 100 mgwk21 of
testosterone enanthate to elderly men over 12 weeks
(combined with resistance training) and reported that
testosterone replacement did not augment gains in muscle
strength and lean body mass.
The effect of androgens on strength and body mass gains
has not been lost on the medical community. Many diseases
result in weight loss and skeletal muscle atrophy, and the use
of androgens to offset these reductions has been suggested.
Androgen therapy has been used in patients with human
immunodeficiency virus (HIV) infection/AIDS, pulmonary
disorders, liver failure, severe burns, renal failure, and spinal
cord injuries, and during postoperative recovery. Body mass
gains have been common in these studies as a result of
androgen therapy (38,112). For example, Casaburi et al. (102)
administered 100 mgwk21 of testosterone enanthate or
placebo for 10 weeks in patients with chronic obstructive
lung disease (COPD) who were undergoing resistance
training simultaneously, and they reported significantly
greater increases in lower-body strength and endurance in
the testosterone group compared with the placebo group.
Interestingly, lean body mass increased similarly in both
groups receiving the androgens (e.g., 1 sedentary and
1 resistance training). Strawford et al. (485) investigated
the combination of testosterone replacement (100 mgwk21)
plus resistance training with either a placebo or an additional
20 mgd21 of oxandrolone for 8 weeks in patients with HIV
infection, and they reported the oxandrolone group increased lean tissue mass and several measures of muscle
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strength to a greater extent than the placebo group. Storer
et al. (483) and Bhasin et al. (65) also reported greater
increases in lean body mass and strength in HIV-positive men
after 12 and 16 weeks of nandrolone (150 mgwk21) and 100
mgwk21 of testosterone enanthate administration, respectively. Interestingly, the addition of resistance training did not
augment muscle strength or lean body mass gains when 100
mgwk21 of testosterone enanthate was administered (65).
Bhasin et al. (62) showed 12 weeks of testosterone administration via transdermal patch (2.5 mg every 24 hours) in the
absence of resistance training increased lean tissue mass (but
not muscle strength) to a greater extent than a placebo in
HIV-positive men.
Clinical Applications of Androgens
Testosterone is approved for the treatment of hypogonadism
in adult men. The reader is referred to the guidelines for the
use of testosterone therapy in hypogonadal men developed
by an expert panel of the Endocrine Society (59). Substantial
pharmaceutical effort is currently focused on exploiting the
anabolic effects of androgens on the skeletal muscle for the
prevention and treatment of sarcopenia and functional
limitations associated with aging and chronic illness (57),
although androgens are currently not approved for these
indications.
Testosterone Therapy of Androgen-Deficient Men. Testosterone
replacement therapy has been approved by the Food and
Drug Administration for the treatment of androgen
deficiency syndromes in adult men (59). In young androgen-deficient men, testosterone therapy has many benefits
and is associated with a low risk of serious adverse events.
Consequently, an expert Panel of the Endocrine Society
recommended testosterone therapy for symptomatic men
with classical androgen deficiency syndromes who have low
testosterone levels (59).
In a systematic review of mostly open-label trials in healthy,
androgen-deficient men, testosterone therapy was associated
with significant gains in FFM and maximal voluntary strength
and a significant decrease in whole-body fat mass (57).
Testosterone administration in hypogonadal men also
increases vertebral bone mineral density (59). However, its
effects on fracture risk are unknown.
Testosterone improves many domains of sexual function in
hypogonadal men (60). Testosterone therapy increases
spontaneous sexual thoughts and fantasies, overall sexual
activity scores and sexual desire (7,24,311,462,476), and
attentiveness to erotic stimuli (6). Testosterone administration in healthy, hypogonadal men increases the frequency
and duration of nocturnal penile erections (127). Testosterone therapy does not alter the erectile response to visual
erotic stimulus (311) or frequency of orgasms in hypogonadal
men (59), although it increases the volume of the ejaculate.
The effects of testosterone on mood and sense of well-being
have not been well studied. Anecdotally, androgen-deficient
men report improvements in sense of well-being and energy
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after initiation of testosterone therapy. Testosterone
replacement in hypogonadal men improves positive aspects
and reduces negative aspects of mood (522). However,
randomized clinical trial data on the effects of testosterone
therapy on mood are limited and have not shown significantly greater improvements in mood with testosterone
therapy than with placebo (476). Some studies have reported
small and inconsistent effects of testosterone on visuospatial
cognition and verbal memory and verbal fluency (106,261).
Studies of the effects of testosterone therapy on insulin
sensitivity have yielded conflicting results (249,281,343,
344,456). Although low testosterone levels in cross-sectional
studies of community-dwelling men have been associated
with increased risk of insulin resistance and type 2 diabetes
mellitus, testosterone therapy has not been shown consistently to improve insulin sensitivity or risk of diabetes
mellitus in randomized clinical trials.
Adverse Events Associated With Testosterone
Replacement Therapy. There is an agreement that
testosterone therapy of young hypogonadal men is associated
with a low frequency of adverse events (59). Acne and oiliness
of skin are common in young hypogonadal men. Erythrocytosis is the most frequent and dose-limiting adverse
event associated with testosterone therapy in testosterone
trials (59). The increments in hematocrit during testosterone
therapy are related to testosterone dose and age (122); older
men experience greater increments in hemoglobin and
hematocrit than young men (122).
The frequency of the development of gynecomastia in
testosterone-treated men is low. Testosterone has been
reported to induce and worsen obstructive sleep apnea.
Patients with obstructive sleep apnea have a high frequency of
low testosterone levels and testosterone therapy has also been
reported to improve sleep apnea.
Testosterone therapy in young hypogonadal men increases
prostate-specific antigen (PSA) levels by an average 0.3
ngmL21 and in older hypogonadal men by 0.43 ngmL21
(95). However, PSA levels do not increase progressively
during continued testosterone therapy (46,350). Similarly,
hypogonadal men have smaller prostate volumes than agematched eugonadal controls (46,350). After initiation of
testosterone therapy, prostate volume increases to that seen
in age-matched eugonadal controls. There is no evidence
that testosterone therapy worsens lower urinary tract
symptoms or causes prostate cancer. However, testosterone
administration might promote the growth of metastatic
prostate cancer. Many older men harbor subclinical prostate
cancers in their prostate; there is concern that testosterone
therapy of older men might induce these subclinical cancers
to grow and become clinically overt (59,61). Testosterone
therapy is associated with increased risk of prostate biopsy
and detection of prostate events (59,61).
Contraindications for Testosterone Therapy. Testosterone therapy is contraindicated in men with prostate and
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breast cancer (59). Testosterone is associated with high risk of
serious adverse events in men with erythrocytosis, untreated
severe sleep apnea, severe lower urinary tract symptoms as
indicated by AUA/IPSS symptom score greater than 19, or
class III or IV congestive heart failure. Testosterone therapy
should not be initiated in individuals with undiagnosed
prostate nodule or induration or PSA more than 3 ngmL21
without appropriate urological evaluation (59).
Monitoring of Testosterone Therapy. The goal of
testosterone therapy is to raise testosterone levels into the
mid-normal range for healthy young men, correct symptoms
of androgen deficiency, induce and maintain secondary sex
characteristics, and maintain sexual function (59). Testosterone levels should be measured 3 months after initiating
testosterone therapy and the dose and/or regimen adjusted
to achieve testosterone levels in the mid-normal range.
To minimize risks and for early detection of adverse events,
the Endocrine Society Expert Panel recommended that
patients receiving testosterone therapy should have their
hematocrit and serum PSA, and AUA/IPSS prostate symptoms score measured before initiating therapy, 3 months after
starting therapy, and annually thereafter (59). The patients
should also undergo digital prostate examination at baseline,
after 3 months of therapy, and annually thereafter. Androgendeficient men should undergo a dual x-ray absoriptiometry
(DEXA) scan to measure baseline bone mineral density;
patients deemed osteoporotic should have their bone mineral
density measured again by DEXA scan 1 or 2 years after
initiating testosterone therapy.
Testosterone Therapy for Sexual Dysfunction. Many
domains of male sexual function are regulated by testosterone
(60). Pioneering investigations have demonstrated that
androgen-deficient men can achieve penile erections in
response to erotic stimuli, but their overall sexual activity is
decreased (332,476). Testosterone increases sexual thoughts,
desire (311), arousal, and attentiveness to erotic stimuli (6).
Testosterone administration increases the frequency, fullness,
and duration of nocturnal penile tumescence (96). Maximum
rigidity may require a threshold level of androgen activity
(92): testosterone regulates nitric oxide synthase (NOS) in
the cavernosal smooth muscle (332) and exerts trophic
effects on cavernosal smooth muscle (446) and ischiocavernosus and bulbospongiosus muscles, and is necessary for the
veno-occlusive response. However, testosterone does not
improve erectile response to visual erotic stimulus (311) or
erectile function in men with erectile dysfunction who have
normal testosterone levels or orgasms (258).
Androgen deficiency and erectile dysfunction are 2
independently distributed disorders that coexist in 6–10%
of middle-aged and older men (300). Testosterone trials
among sildenafil failures have been inconclusive (26,447).
There is insufficient evidence to support the proposal that
testosterone improves therapeutic response to selective
phosphodiesterase inhibitors (26,59,447).
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Table 4 provides the domains of sexual function that are
improved by androgen therapy in hypogonadal men.
Systematic reviews of randomized trials have shown that
testosterone therapy improves sexual activity and libido in
men with sexual dysfunction who have unequivocally low
testosterone levels but not in men with normal testosterone
levels. These considerations led the Endocrine Society
Expert Panel to ‘‘suggest (that) clinicians offer testosterone
therapy to men with low testosterone levels and low libido in
order to improve libido and to men with erectile function
(ED) who have unequivocally low testosterone levels after
evaluation of underlying causes of ED and consideration of
established therapies for ED)’’ (59). However, the expert
panel noted the low-quality evidence supporting this
suggestion.
Anabolic Applications of Androgens for the
Prevention and Treatment of Sarcopenia and
Functional Limitations Associated With Aging and
Chronic Illness. Administration of supraphysiologic doses
of testosterone increases skeletal muscle cross-sectional area,
lean body mass, and maximal voluntary muscle strength in
eugonadal young men (Figure 3) (63). Subsequent research
has shown that the anabolic effects of testosterone on
appendicular skeletal muscle mass, muscle size, and maximal
voluntary strength are correlated with the administered dose
and circulating testosterone concentrations (Figure 4) (68).
This section will review possible clinical applications of
testosterone therapy to treat the muscle wasting and
functional limitations associated with aging and chronic
diseases.
Mechanisms of Testosterone Effects on the Skeletal Muscle.
Testosterone-induced increase in skeletal muscle mass is
associated with hypertrophy of both type I and type II fibers
(460) and an increase in the number of myonuclei and satellite
cells (461). Testosterone promotes the differentiation of
mesenchymal multipotent cells into the myogenic lineage
and inhibits their differentiation into the adipogenic lineage
(66,459). Androgens regulate mesenchymal multipotent cell
differentiation by binding to AR and promoting the
association of AR with b-catenin and translocation of the
TABLE 4. Domains of sexual function that are
improved by testosterone therapy of androgendeficient men.*
1.
2.
3.
4.
Spontaneous sexual thoughts
Attentiveness to erotic auditory stimuli
Frequency of nighttime and daytime erections
Duration, magnitude, and frequency of nocturnal
penile erections
5. Overall sexual activity scores
6. Volume of ejaculate
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AR–b-catenin complex into the nucleus, resulting in activation
of TCF-4 (458). The activation of TCF-4 modulates a number
of Wnt-regulated genes that promote myogenic differentiation
and inhibit adipogenic differentiation (458).
Testosterone also inhibits preadipocyte differentiation into
adipocytes (458). The effects of testosterone on myogenic
differentiation in vitro are blocked by the AR antagonist,
bicalutamide, indicating that these effects are mediated
through an AR pathway (458). It is possible that androgens
might exert additional effects through nongenomic mechanisms. Testosterone increases fractional muscle protein
synthesis and improves the reutilization of amino acids by
the muscle (180–182,447).
We do not know whether conversion of testosterone to
DHT or to estradiol 17-b is required for mediating androgen
effects on the muscle. Steroid 5-a reductase (SRD5A2), which
converts testosterone to DHT, is expressed at low concentrations in skeletal muscle, but individuals with congenital
SRD5A2 deficiency have normal muscle development at
puberty.
Androgen Therapy in Chronic Diseases. Low testosterone is
a common feature of many chronic diseases in men and is
associated with loss of muscle mass and strength, bone density,
sexual dysfunction, and loss of energy (276). The observations
that androgen replacement or supplementation unequivocally
increases FFM, total body mass, and maximal voluntary
strength in hypogonadal men and healthy, eugonadal young
and older men have led to the hypothesis that androgens
might be useful in treating the loss of muscle and physical
function seen in patients with chronic diseases such as HIV
infection with wasting syndrome, COPD, and end-stage renal
disease (ESRD).
Testosterone Therapy for HIV-Infected Men With Weight Loss.
There is a high prevalence of low testosterone levels in
HIV-infected men, even among those receiving highly
active antiretroviral therapy (25,153,423). Serum testosterone
levels are lower in HIV-infected men with weight loss (120)
and correlate with deficits in muscle mass and strength
(65,62,215,483), low Karnofsky scores (25), depressed mood,
and disease progression (218,412,433).
Some of the studies that have examined the effects of
androgen administration on body weight and composition in
HIV-infected men were not placebo controlled (54,205,235,
413) and most failed to control energy intake and exercise
stimulus. Three placebo-controlled studies of testosterone
supplementation of HIV-infected men (62,65,482) reported
gains in FFM, whereas others (119,152) did not. Significantly
greater improvements in maximal voluntary strength have
been shown in HIV-infected men treated with androgens vs.
placebo (65,216,217,485). In a recent meta-analysis, testosterone therapy had a moderate effect on depression (20.6 SD
units, 95% confidence interval [CI] 21.0, 20.2), but no significant testosterone effect on quality of life (58). There were no
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Mid-arm area (468), mid-thigh
cross-sectional area (345), and
quadriceps strength (490) have
been shown to be predictors of
mortality in patients with
COPD. Peripheral muscle weakness in patients with COPD is
associated with increased utilization of health care resources
(131). Proposed mechanisms of
skeletal muscle dysfunction in
COPD are numerous and include disuse atrophy, systemic
inflammation, oxidative stress,
blood gas abnormalities, and
use of glucocorticosteroids
(11,100,101,421,521).
Several
studies have reported higher
prevalence of low testosterone
in men with COPD than in
healthy older men (100,101,
513), although a study reported
frequency of low testosterone
levels to be no greater than
healthy age-matched controls
Figure 3. Changes from baseline in mean (6SE) fat-free mass (a) and muscle strength in the bench press (b) and
squatting exercises (c) over the 10 weeks of treatment with 600 mgwk21 testosterone enanthate (TE). The p values
(312).
shown are for the comparison between the change indicated and a change of zero. *p , 0.05 for the comparison
Resistance exercise training
between the change indicated and that in either no-exercise groups; †p , 0.05 for the comparison between the
improves
skeletal
muscle
change indicated and that in the group assigned to placebo with no exercise; ‡p , 0.05 for the comparison
between the change indicated and the changes in all 3 other groups. Modified from Bhasin et al. (65).
strength (56,102,400,455,480)
and leg extensor power in
patients with COPD (245).
Only scant evidence (400),
significant differences in adverse event rates or changes in
however, suggests that these changes result in improvement
CD4+ T lymphocyte counts, HIV viral load, PSA, and plasma
of physical function. Recent evidence-based guidelines for
HDL cholesterol between testosterone- and placebo-treated
pulmonary rehabilitation (371,422) have emphasized the
men with HIV infection (58).
value of resistance exercise training for increasing muscle
Testosterone trials in HIV-infected men have been small
strength and muscle mass for both upper and lower
and characterized by heterogeneity across trials. There are
extremities.
no data on testosterone’s effects on physical function and risk
Five studies, including 4 randomized placebo-controlled
of disability or its long-term safety. Overall, short-term (3–6
trials, have investigated the effect of androgens in patients
months) testosterone use in HIV-infected men with low
with COPD (102,125,183,438,542). Schols et al. (438)
testosterone levels and weight loss can lead to small gains in
reported a 1.5 kg weight gain over 8 weeks in 217 men
body weight and lean body mass (LBM) with minimal change
and women with COPD. Subjects receiving nandrolone
in quality of life and mood. This inference is weakened by
decanoate (women, 25 mg; men 50 mg) plus nutritional
inconsistent results across trials. These considerations led the
and exercise interventions increased FFM to a greater extent
Endocrine Society Expert Panel to ‘‘suggest (that) clinicians
than those receiving placebo plus the nutritional supplement
consider short-term testosterone therapy as an adjunctive
and exercise (p , 0.03). Fat mass increases accounted for
therapy in HIV-infected men with low testosterone levels and
most of the weight gain in the placebo group. No differences
weight loss in order to promote weight maintenance and gains
in respiratory muscle strength between groups were noted.
in LBM and muscle strength’’ (59). The evidence supporting
Similarly, Creutzberg and et al. (125) showed that men with
this suggestion is of moderate quality.
COPD receiving 8 weeks of biweekly injections of 50 mg
nandrolone decanoate experienced significantly greater increase in DEXA-determined FFM when compared with
Chronic Obstructive Pulmonary Disease. Patients with COPD
controls, 1.7 6 2.5 vs. 0.3 6 1.9 kg, respectively. Muscle
have weak muscles (55,209,480) with smaller cross-sectional
function and exercise capacity improved to the same extent
area (55) than age- and gender-matched healthy individuals.
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Figure 4. Changes from baseline in fat-free mass (a) and leg press
strength (b) in young (n) and older ( ) men in response to graded doses
of testosterone enanthate. Healthy, young, and older men were
randomized to receive a long-acting gonadotropin-releasing hormone
agonist plus one of 5 different doses of testosterone enanthate (25, 50,
125, 300, and 600 mg weekly, intramuscularly) for 20 weeks. Changes in
other outcome measures were calculated as the difference between
week 20 and baseline values. Data are the mean 6 SEM. If there were
a significant age effect, the values for young and older men for each dose
were compared using Tukey’s multiple comparison procedure. Similarly, if
the linear model revealed a significant dose effect, then different dose
groups were compared using Tukey’s multiple comparison procedure.
#significant difference from 25- and 50-mg doses (p , 0.05). Modified
from Bhasin et al. (68).
in both groups. Ferreira et al. (183) reported that underweight
patients with COPD increased lean body mass by 2.5 kg
after 6 months of treatment with 12 mgd21 oral stanozolol.
Neither the stanozolol nor the control group demonstrated
functional improvements or changes in maximum inspiratory
pressure. In a multicenter, open-label trial of oral oxandrolone in men and women with COPD, Yeh et al. (542) showed
an average 2.1 kg weight gain (1.6 kg lean mass) after
4 months of treatment. Neither spirometry nor 6-minute
walk distance changed significantly.
Casaburi et al. (102) were the first to demonstrate
significant increases in muscle performance, as well as
increases in lean body mass after androgen administration
in men with COPD. Using a 2-by-2 factorial design, 47 men
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with moderate to severe COPD (mean forced expiratory
volume in the first second of expiration = 40% of predicted)
and low testosterone (mean = 320 ngdL21) were randomized to one of 4 groups in a 10-week study: resistance exercise
training only, resistance training + placebo, resistance
training + 100 mgwk21 testosterone enanthate, or 100
mgwk21 testosterone enanthate only. Men receiving testosterone had mean nadir levels within the mid-range of young
healthy men. Leg press strength increased 17% in the men
receiving testosterone alone and in the resistance training
plus placebo groups; leg press strength improved 27% in the
combined group. Leg press fatigability (repetitions to failure
at 80% 1RM) increased by 2, 7, and 11 repetitions, in the
testosterone only, resistance training + placebo, and
combined groups, respectively. Lean body mass increased
2.3 kg in the testosterone-only group and 3.3 kg in the group
receiving testosterone + resistance exercise training. No
changes in lean body mass were noted in the men who only
performed resistance training only. Thus, 10 weeks of
a replacement dose of testosterone in men with moderate
to severe COPD yielded significant improvements in lean
body mass, muscle strength, and resistance to fatigue.
Resistance training of the legs resulted in benefits similar
to testosterone and the combination of the interventions
proved to be additive.
Increased strength and resistance to fatigue might prove
valuable in maintaining physical function required in activities
of daily living. Because muscle cross-sectional area predicts
mortality in patients with COPD (345), interventions that
stimulate increased muscle mass would be expected to
improve outcomes. However, small sample size, substantial
heterogeneity across trials, relatively small androgen doses,
and the lack of inclusion of patient-important outcomes in
these trials contributed to the weak quality of available
evidence and preclude a general recommendation about
testosterone therapy in men with COPD at this time.
Testosterone Therapy in Glucocorticoid-Treated Men. Glucocorticoid administration in pharmacologic doses is associated
with muscle atrophy and a high frequency of low testosterone
levels (278,336,416,417) due to suppression of all components
of the hypothalamic-pituitary-testicular axis. In 2 randomized
placebo-controlled trials (54,418), testosterone supplementation of men receiving glucocorticoid treatment for
bronchial asthma or chronic obstructive pulmonary disease
was associated with an average 2.3 kg (95% CI 2.0–3.6)
greater gain in lean body mass and a greater decrease in fat
mass (contrast 23.1 kg, 95% CI 23.5, 22.8) than placebo
(57). These 2 trials (54,418) found an increase in bone mineral
density in the lumbar spine (+4%, 95% CI 2–7%); the effect
on femoral bone density was inconsistent and not significant
(57). There are no data on the effects of testosterone
supplementation on bone fractures in glucocorticoid-treated
men. Testosterone administration was associated with a low
frequency of mild adverse events (124,418). Based on
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Androgen and Human Growth Hormone Use
such data, the Endocrine Society Expert Panel suggested (59)
that ‘‘clinicians offer short-term testosterone therapy to men
receiving high doses of glucocorticoids who have low
testosterone levels in order to promote preservation of
LBM and bone mineral density’’ (59). These inferences are
weakened by the small size of the studies, high rates of loss to
follow-up in 1 study, and inconsistent results (57,59).
End-Stage Renal Disease. Approximately two-thirds of men
receiving dialysis for treatment of chronic renal failure have
low testosterone levels (3,457). Hypogonadism in men with
ESRD has been associated with sexual dysfunction (385),
osteoporosis risk (3), anemia (86), and malnutrition (189).
Carotid artery intimal thickness and presence of atherosclerotic plaque have been shown to be negatively correlated with
serum testosterone levels in patients with ESRD but positively
related to endothelium-dependent vasodilation (282).
Exercise intolerance and malaise are common problems
among many individuals undergoing maintenance hemodialysis (MHD) (252). Studies of exercise capacity and training
in these patients frequently report low exercise tolerance
(32,263,384,481), muscular weakness, low physical activity
levels (268), and impaired physical function (73,266,267,
271,299). Johansen et al. (271) have demonstrated that
dialysis patients have significantly greater contractile area
atrophy compared with healthy controls, even when
corrected for habitual activity level. The muscle atrophy
was associated with muscle weakness and reduced gait speed
(271). Abnormalities in muscle function and physical
performance begin early in the course of chronic kidney
disease (CKD), become progressively worse as the disease
progresses (318), and are a major determinant of selfreported quality of life in patients with ESRD (111).
Functional limitations in patients with ESRD are undoubtedly multifactorial; low levels of anabolic hormones
such as testosterone and GH, physical inactivity, uremic
myopathy, malnutrition, and carnitine deficiency have been
proposed as contributors (138,271,299,302).
Strategies to increase muscle mass and strength are
attractive because they would be expected to improve
physical function and quality of life. Exercise training
including endurance training, resistance training, and their
combination, and androgens are possible approaches that
may be used to overcome muscle atrophy and weakness.
Johansen et al. (269) demonstrated that 6 months of weekly
injections of 100 mg nandrolone decanoate significantly
increased lean body mass by 4.5 6 2.3 kg compared with the
1.9 6 0.6 kg change in the placebo group. Muscle mass
increases were observed only in the nandrolone-treated men.
Combined times for completing walking and stair climbing
tasks decreased by 3.8 seconds in the treated group
compared with a 3.4-second increase in control subjects;
these differences were statistically significant. There were
no differences in the change in grip strength between the
2 groups.
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In a recent 12-week, randomized controlled trial of
nandrolone decanoate (100 mgwk21 for women, 200
mgwk21 for men) or placebo with or without resistance
exercise training, Johansen et al. (270) confirmed their earlier
findings of significantly increased LBM, 3.3 6 2.0 kg with
nandrolone treatment alone. The subjects receiving nandrolone in combination with resistance training also experienced
significant gains in LBM, 3.0 6 2.4 kg. Lean body mass did not
change in either of the placebo-controlled groups. Quadriceps
cross-sectional area increased significantly in both the
nandrolone and exercise groups relative to the controls and
was additive in the combined treatment group. Trainingspecific 3RM strength measures for the lower extremity
improved only in the groups receiving resistance training.
These effects on muscle size, strength, and body composition
were not different between men and women. Neither
intervention, alone or in combination, produced significant
changes in measures of physical function, for example, gait
speed, stair climbing, or chair stands. It is possible that the
short study duration may have not allowed sufficient time for
the neuromuscular adaptations that are necessary for translation of muscle mass and strength gains into functional
improvements. Self-reported improvements in physical function were noted in the resistance-trained group but not in the
nandrolone group. The doses of nandrolone decanoate used in
this study were well tolerated. With 79 patients randomized
(49 men) and an 86% completion rate, this was the largest
randomized controlled trial to date using androgens or
resistance exercise training in patients undergoing MHD.
Even so, the study may not have had sufficient power to detect
clinically meaningful changes in measures of physical function.
Eiam-Ong et al. (162) randomized 29 predialysis patients
with CKD in a 3-month investigation of the anabolic effects
of nandrolone decanoate. Subjects received either conventional treatment for CKD or conventional treatment plus
weekly injections of 100 mg nandrolone. Lean body mass
increased significantly greater in the nandrolone-treated
group as compared with controls, 2.1 6 2.2 vs. 0.4 6 1.4 kg,
respectively. The authors concluded that 100 mgwk21
nandrolone decanoate significantly improved lean body
mass without altering renal function or producing serious
adverse effects in these patients.
The ideal dose of nandrolone decanoate for anabolic
effects in patients with chronic kidney failure has not been
determined, and there is only limited evidence that changes in
muscle size and strength in these patients can translate into
functional improvements after androgen administration.
Improvements in self-reported physical function, although
not currently seen in studies of hemodialysis patients
receiving androgen administration, are nevertheless important with respect to its association with lower morbidity
and mortality in these patients (330). Additional adequately
powered studies are needed to determine whether long-term
treatment with androgens is safe and effective in improving
physical function (both measured and self-reported),
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mobility, and health-related outcomes, and in reducing
morbidity and mortality in patients with ESRD.
Testosterone Therapy for Older Men With Sarcopenia and
Functional Limitations. Cross-sectional as well as longitudinal
studies are in agreement that total and free testosterone
concentrations decline progressively with advancing age
(32,128,178,184,212,228,363,401,404,454,550). In the Baltimore Longitudinal Study on Aging, 20% of men older than
60 years and 50% of men older than 80 years had total
testosterone levels in the hypogonadal range (total testosterone less than 325 ngdL21) (228). Because SHBG concentrations are higher in older men than in young men (178,401),
free testosterone concentrations decline to a greater extent
than total testosterone concentrations. The age-related
decline in testosterone concentrations is the result of defects
at all levels of the hypothalamic-pituitary-testicular axis.
In epidemiological studies (44,45,354,361,376,382,394,428,
436,510), low total or bioavailable testosterone levels are
associated with low appendicular skeletal muscle mass
and muscle strength and self-reported physical function.
Low testosterone levels have also been associated with
decreased self-reported and performance-based physical
function in a number of epidemiologic studies (130,361,376,
382,436,510). The data on the association of testosterone
levels with sexual dysfunction have been inconsistent
(17,275,300,341,502,549). In general, serum total and bioavailable testosterone levels are not significantly different
between men who report erectile dysfunction and those who
do not (275,300). In the Massachusetts Male Aging Study
(MMAS), decreased libido, as assessed by a single question,
was associated only with very low testosterone levels (502).
In another study of men older than 50 years who had benign
prostatic hyperplasia, sexual dysfunction, assessed by the
Sexual Function Inventory, was reported only in men with
serum total testosterone levels less than 225 ngdL21 (341).
Age-related declines in verbal memory, visual memory, spatial
ability, and executive function are associated with the age-related
decline in testosterone (6,35,109,177,210,240,260,261,452,496).
The relationship of testosterone levels with depression has
been inconsistent across epidemiologic studies (36,137,342,
443,444,511). Low testosterone levels in older men appear
to be associated more with subsyndromal depression and
related symptoms than with major depression (443,444). In
one study, testosterone levels were lower in older men with
dysthymic disorder than in those without any depressive
symptoms (443). In another study, men with low testosterone levels had higher Carroll Rating Index scores, indicating
more depressive symptoms than those who had normal
testosterone levels (137).
Several epidemiologic studies of older men (12,165,214,
317,354), including MrOS (165), the Rancho Bernardo Study
(214), the Framingham Heart Study (12), and the Olmsted
County Study (354), have found bioavailable testosterone
levels to be associated with bone mineral density, bone
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geometry, and bone quality (317); the associations are
stronger with bioavailable testosterone and estradiol levels
than with total testosterone levels. In the MrOS Study, the
odds of osteoporosis in men with a total testosterone less
than 200 ngdL21 were 3.7-fold higher than in men with
normal testosterone level (165); free testosterone was an
independent predictor of prevalent osteoporotic bone
fractures (352).
Several recent studies have evaluated the association of
testosterone levels and mortality; 2 Veterans Administration
(VA) studies (450,451) and the Rancho Bernardo Study (316)
found higher overall all-cause mortality in men with low
testosterone levels than in those with normal testosterone
levels, but testosterone levels were not correlated with
overall mortality in the MMAS (18). In the Rancho Bernardo
Study, men in the lowest quartile of testosterone levels
(,241 ngdL21) were 40% more likely to die over the next
20 years than those with higher levels (316). The increased
risk of death in men with low testosterone levels was
independent of multiple risk factors, including age, adiposity,
and lifestyle (316).
Testosterone levels are not correlated with aging-related
symptoms assessed by the Aging Male Symptom score
or with lower urinary tract symptoms assessed by the
AUA/IPSS prostate symptom questionnaire (323). A number
of cross-sectional studies also found no difference in serum
testosterone levels between men who had coronary artery
disease and those who did not have coronary artery disease;
other studies have reported testosterone levels or to be lower
in men with coronary artery disease than in men without
coronary artery disease (8,34,118,222,540). A cause and effect
relationship cannot be inferred from these epidemiological
studies, especially cross-sectional studies. Furthermore, even
the associations between testosterone levels and healthrelated outcomes that have been found to be statistically
significant are weak.
The risks and health benefits of long-term testosterone
remain poorly understood. Overall, testosterone trials in older
men have been characterized by small sample size, inclusion
of healthy older men with low or low-normal testosterone
levels who were asymptomatic, and the use of surrogate
outcomes; these studies did not have sufficient power to
detect meaningful gains in patient-important outcomes and
changes in prostate and cardiovascular event rates (13,72,85,
163,182,290,365,383,453,465,497,506,534).
In a systematic review of randomized trials (57), testosterone therapy was associated with a significantly greater
increase in FFM (contrast 2.5 kg, 95% CI 1.5–3.4) and right
hand grip strength (contrast 3.3 kg, 95% CI 0.7–5.8 kg)
(Figure 5). Whole-body fat mass showed a greater reduction
in androgen groups (contrast 22.1 kg, 95% CI 23.1, 21.1)
than in placebo (163,182,290,364,383,465,497,534).
Testosterone therapy also improves self-reported physical
function, assessed by the physical function domain of MOS
SF-36 questionnaire (0.5 SD units, 95% CI 0.03–0.9) (57,59).
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However, the effects of testosterone replacement on
quadriceps strength, leg power, muscle fatigability, and
physical function in older men have been inconsistent across
trials, and its effects on risk of disability and falls have not
been studied (39,163,365,383). Testosterone replacement
increases lumbar bone mineral density but not femoral bone
mineral density in older men with low testosterone levels
(13,290,465), but we do not know whether testosterone
reduces fracture risk. Testosterone replacement improves
sexual function in older men with low testosterone levels
(74,254) but not in men with erectile dysfunction who have
normal testosterone levels. Testosterone therapy has been
shown to improve visual-spatial skills, verbal memory, and
verbal fluency in older men with low testosterone levels in
some but not in all trials. It is unknown whether testosterone
supplementation can induce clinically meaningful changes in
cognitive function in older men. The effects of testosterone
replacement on vitality and health-related quality of life have
not been studied. Short-term administration of testosterone
in replacement doses is safe, but the long-term risks of
testosterone administration in older men remain unknown.
The potential adverse effects of testosterone in older men
include the risk of erythrocytosis, induction or exacerbation of
sleep apnea, gynecomastia, and clinically detectable prostate
events. Testosterone administration by increasing the intensity of PSA surveillance will likely lead to increased
number of prostate biopsies and increased detection of
prostate cancers (95). It is possible that testosterone
administration might make subclinical foci of prostate cancer
grow and become clinically overt; we do not know what
clinical impact this would have on patient morbidity and
survival and health care costs (57,59). Because the efficacy
of testosterone supplementation on health-related outcomes
has not been demonstrated and its risks remain largely
unknown, an expert panel of the Endocrine Society
concluded that the available data did not permit a general
recommendation about testosterone therapy for all older
men with low testosterone levels (59). The panel suggested
that until more information becomes available, testosterone
administration in older men should be individualized and
limited only to older men with unequivocally and consistently low testosterone levels who are experiencing significant symptoms of androgen deficiency; in these individuals,
consideration of testosterone therapy should be preceded by
a careful discussion of its potential risks and benefits with the
patient and rigorous monitoring of potential adverse effects
(59). An expert panel of Institute of Medicine on the Future
Direction of Testosterone Research deemed this a priority
area for further research and recommended coordinated
trials of testosterone therapy in symptomatic older men in
4 efficacy areas: physical dysfunction, sexual dysfunction,
vitality, and cognitive dysfunction (325).
Figure 5. Changes in LBM and grip strength. Meta-analysis plots of contrasts between testosterone-treated and placebo-treated men older than 45 years. (a) The
change in lean body mass (kg). (b) The change in right hand grip strength. A positive difference indicates a favorable testosterone effect. Confidence intervals that
do not overlap with zero represent significant differences between placebo and testosterone groups. Modified from Bhasin et al. (58).
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Dosing and Use Patterns of Androgens in Athletic
Populations
Androgens are typically used by athletes in a ‘‘stacking’’
fashion, in which several different drugs are administered
simultaneously. The basis for stacking is that the potency
of one anabolic agent may be enhanced when consumed
simultaneously with another anabolic agent. Athletes will
typically use both oral and parenteral (injectable) compounds;
however, the administration of androgens via injection
appears to be the most common method of self-administration (as indicated by 77% of androgen users) (114). The
primary reason for using parenteral compounds is thought to
be related to health reasons and the belief that this route of
administration results in greater results (114). Most users will
take androgens in a cyclic pattern, meaning they will use
the drugs for several weeks or months and alternate these
cycles with periods of discontinued use. Often athletes will
administer the drugs in a pyramid (step-up) pattern in which
dosages are steadily increased over several weeks. Toward
the end of the cycle, the athlete will ‘‘step down’’’ to reduce
the likelihood of negative side effects. At this point, some
athletes will discontinue drug use or perhaps initiate another
cycle of different drugs (i.e., drugs that may increase
endogenous testosterone production to prevent the undesirable drop in testosterone concentrations that follows the
removal of the pharmaceutical agents). Although the length
of each cycle is quite variable (ranges from 1 to 728 weeks),
the median cycle length is reported to be 11 weeks (114).
Recent surveys have indicated that the typical nonmedical
use pattern is 4–6 months in a year (114,388). A typical
androgen regimen involves 3.1 agents, and the dose being
administered is reported to vary between 5 and 29 times
greater than physiological replacement doses (395). Nearly
50% of individuals who self-administer androgens exceed
1,000 mg of testosterone or its equivalent per week (388).
However, this number may be exaggerated, as Cohen et al.
(114) in a more recent survey suggested that the number of
androgen users who self-administer more than 1,000 mg of
testosterone or its equivalent per week may be closer to 10%.
Regardless, the higher pharmacologic dosages common
among androgen users do appear to be important for eliciting
the gains that these individuals desire. The importance of
dose has been clearly demonstrated in a classical study
published by Forbes in 1985 (187), in which total dose of
androgens administered was shown to have a logarithmic
relationship to increases in lean body mass. These results
provide fuel to the more is better philosophy employed by
many athletes using performance-enhancing drugs.
Another issue associated with androgens use is the
polypharmacy that is often seen among individuals who
self-administer these drugs. A recent study indicated that 96%
of androgen users (481 of 500) admitted to using other
anabolic agents and/or stimulants to exacerbate the performance gains or medications to reduce the side effects
associated with androgen use (388). The most common type
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of accessory medication used by these individuals appears to
be compounds designed to promote fat loss. More than 65%
of users admit to using caffeine and ephedra/ephedrine
during their drug cycle. In addition, one of every 4 individuals
who admit to self-administering androgens also indicated
that they concomitantly use GH, insulin, or IGF during their
drug cycle (388). More than half of individuals who selfadminister androgens also use medications to reduce or
prevent side effects generally associated with androgen abuse
(388).
Masking Agents and Drugs Commonly Used with Androgens
In many cases, androgens are consumed along with other
drugs as part of a ‘‘stack’’ or to mask steroid use in preparation
for drug testing. Likewise, these drugs are banned substances
that can result in a positive drug test and subsequent
punishment. The following section briefly examines some
other drugs that athletes may use in addition to androgens
and hGH.
Masking Agents. Masking agents are used to produce negative
drug testing results by hiding the use of androgens and other
drugs. In some cases, diuretics have been used to dilute urine
and mask drug use. Sulfonamides decrease the excretion
rate of various drugs and are used to slow the excretion rate
of androgens metabolites. However, these drugs were
more effective when drug testing was more primitive in its
development. Current drug tests can detect anabolic steroids
in the urine despite the use of sulfonamides. One commonly
used sulfonamide, probenecid, has been added to the banned
substances list, and its use has declined dramatically among
athletes. Probenecid was developed in the 1950s to reduce the
excretion of penicillin. Detection of probenecid results in
a failed drug test and possible suspension.
Some athletes have also used epitestosterone as a masking
agent (2). Epitestosterone is 17a epimer of testosterone found
in urine in similar concentrations to testosterone. Although
its physiological role is unclear (e.g., possible antiandrogenic
activity) (474), some athletes have administered epitestosterone (in similar doses to their testosterone regimen) to reduce
the T:E ratio to within legal limits (i.e., a 4:1 ratio). Reports
from athletes have indicated that epitestosterone injections
1 hour before testing have resulted in a ‘‘passed’’ drug test.
Although epitestosterone administration can be detected (2),
it could result in an athlete passing a drug test unless it is
specifically tested for. Epitestosterone is difficult to obtain
commercially so it is mostly used by elite athletes. Last, other
masking procedures such as urine substitution, catheterization, use of adulterants, and other tampering methods have
been reported (257). These procedures are banned, and
stricter enforcement policies have been used in an attempt
to decrease their use among athletes.
Diuretics. Diuretics block sodium reabsorption in the kidneys
and induce fluid and electrolyte loss in urine. Diuretics have
been used to treat diseases such as hypertension, congestive
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heart failure, edema, and kidney and liver problems
(80,241,492). Classifications include loop diuretics (block
sodium reabsorption in the loop of Henle in the kidneys, that
is, furosemide, bumetanide, ethacrynic acid, torsemide),
thiazides (block sodium reabsorption at the distal tubule,
i.e., chlorthalidone, hydrochlorothiazide, indapamide, metolazone, trichlormethiazide, quinethazone), and potassium-sparing diuretics (i.e., amiloride, triamterene, spironolactone).
Other types of diuretics exist but are much less commonly
used by athletes. Diuretics induce fluid/weight loss, have
been used as masking agents for androgen tests by athletes
(reduce the concentration of drugs in the urine via rapid
diuresis), and have been used in sports that used weight
classes and bodybuilding. Benzi (53) has reported that
diuretics were the fourth most commonly used drug behind
androgens, stimulants, and narcotics. Diuretics are banned
substances, and urine samples containing diuretic residues
result in a failed drug test.
Diuretics are used in the short-term. They pose many
other serious side effects including fatigue, weakness, muscle
cramps, soreness, headaches, confusion, nausea, loss of
appetite, cardiac arrhythmia, and reduced muscle glycogen.
Studies have shown that 40–126 mg of furosemide resulted
in 2–4% losses in body weight and subsequent reductions in
cycling performance, V_ O2max, muscle strength, and rate of
force development (23). Aerobic exercise performance
appears to be more highly reduced than anaerobic exercise
performance, as some studies have shown some reductions in
strength and power but others have shown no performance
decrement with mild dehydration (33). A recent study has
shown that 40 mg of furosemide (resulting in a 2.2% reduction
in body weight) did not negatively affect 50-, 200-, or 400-m
sprint times or vertical jump height (525).
Antiestrogens. Antiestrogens are drugs that inhibit the effects of
estrogen by inhibiting the enzyme aromatase or by blocking
estrogen receptor action (226). Similar to SARMs, SERMs
have been developed to tissue selectively antagonize estrogen
actions (226). Although antiestrogens have been successfully
used to treat various diseases and ailments, that is, breast
cancer, infertility (40,477), they are taken by athletes to
reduce the aromatizing effects from anabolic steroid use. In
males, antiestrogens may increase endogenous production of
testosterone (226,358), which is why some athletes use them
upon completion or near completion of an androgen cycle.
Some androgens have minimal aromatizing properties (i.e.,
Deca-Durabolin) and some are more potent (i.e., Equipoise,
Dianabol, Halotestin, testosterone) (495), thereby enticing
athletes to use antiestrogens as part of the drug stack.
Differential androgenic effects have also been reported
among use of different testosterone esters, for example,
testosterone enanthate vs. buciclate vs. undecanoate (526).
Several undesirable side effects (i.e., gynecomastia, water
retention, and other health risks) of androgens use are caused
by aromatization into estradiol and other estrogens. Studies
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show substantial elevations in plasma estradiol concentrations with testosterone or anabolic steroid administration
(85,508).
Two categories of antiestrogens include aromatase inhibitors and receptor blockers. Aromatase inhibitors block
aromatization, that is, aminoglutethimide (Cytadren),
exemestane (Aromasin), testolactone (Teslac), formestane
(Lentaron), letrozole (Femara), and anastrozole (Arimidex).
Aromasin is thought to be one of, if not the, most effective
aromatase inhibitors among athletes (326). Selective estrogen
receptor modulators and receptor blockers antagonize
estrogen receptors, that is, clomiphene citrate (Clomid),
tamoxifen citrate (Nolvadex), raloxifene (Evista), and cyclofenil. Clomid is a popular drug used by male bodybuilders
(50–100 mgd21) and is frequently used for 4–6 weeks upon
termination of a steroid cycle. Nolvadex is a popular
antiestrogen used by athletes consumed ;10–30 mgd21.
Cytadren is also popular as athletes have reported use of
250–500 mgd21 (although higher doses may be used for the
cortisol-controlling effect), and cyclofenil has been used
;400–600 mgd21 for ;4–5 weeks after a steroid cycle (326).
Aromatase inhibitors, SERMs, and other antiestrogens such
as Clomid are prescription drugs banned by sport governing
bodies including WADA (537).
Thyroid Drugs. The thyroid gland produces 2 key regulatory
metabolic hormones: triiodothyronine (T3) and thyroxine
(T4). Thyroid hormones produce a multitude of functions
in virtually all cells of the human body including critical
functions in the nervous, bone, and muscular systems;
metabolism; and energy expenditure (82,528). Thyroid drugs
(primarily sodium levothyroxine) are typically used to treat
thyroid insufficiency or hypothyroidism (167,530). Thyroid
hormones are consumed in synergy with other drugs
theoretically to potentiate the anabolic response. Athletes,
especially bodybuilders, have used thyroid drugs to potentially enhance the anabolic growth processes and offset
some negative metabolic effects associated with kilocalorie
restriction. Some thyroid drugs used by athletes include
Cytomel, Triacana, and Synthroid in supraclinical doses
(326). Unsupervised use of thyroid drugs can disrupt the
hypothalamic-pituitary-thyroid axis and produce negative
side effects such as bone and skeletal muscle catabolism,
heart palpitations, agitation, shortness of breath, irregular
heartbeat, sweating, nausea, irritability, tremors, restlessness,
and headaches (113,167). Thyroid drugs are prescription
pharmaceuticals used for medicinal purposes and unethical
when used to enhance athletic performance. There is
a paucity of research examining potential ergogenic effects
of thyroid drugs on athletic performance. Thus, their utility is
unclear and use is contraindicated.
Central Nervous System Stimulants. Stimulants increase central
nervous system activity and increase mental acuity, alertness,
physical energy, thermogenesis, and exercise performance,
for example, muscle strength, endurance, improved reaction
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time, and weight loss (27,449). However, side effects such as
nervousness, anxiety, heart palpations, headaches, nausea,
cardiomyopathy, high blood pressure, and in some rare cases
a stroke may occur. Stimulants include amphetamines,
caffeine, cocaine, and ephedrine. Many stimulants are banned
substances but still are commonly used by athletes (537).
Caffeine, pseudoephedrine, synephrine, and both ephedrine
and methylephedrine (in concentrations ,10 mgmL21) are
not prohibited. Amphetamines release stores of norepinephrine, serotonin, and dopamine from nerve endings and
prevent reuptake that leads to increased amounts of
dopamine and norepinephrine in synaptic clefts (27). The
sympathetic response is greatly enhanced by greater
neurotransmitter availability. The American Medical Association in conjunction with the NCAA began investigating
alleged widespread use of amphetamines by athletes in
1957 (283). Bents et al. (52) showed that 7–16% of collegiate
hockey players reported some past and present use of
amphetamines. Ingested amphetamines are absorbed from
the small intestine and peak blood concentrations occur
1–2 hours after use (27). Stimulant effects may be seen with
10–40 minutes after consumption and may last up to 6 hours.
Amphetamine metabolites are excreted in the urine where
they can be detected (up to 4 days after use) via drug testing.
Ephedra has been used to treat respiratory problems and is
commonly present in pharmaceuticals such as bronchodilators, antihistamines, decongestants, and weight loss products.
Ephedrine use is banned by the NCAA. Because ephedrine
alkaloids are found in common cold medicines, American
collegiate athletes need to be aware that consumption of these
products can result in a failed drug test especially because
some products contain higher quantities of ephedrine
alkaloids than what is reported on the label (504). Chester
et al. (107) showed that use of over-the-counter decongestants containing phenylpropanolamine and pseudoephedrine
for 36 hours resulted in peak drug urine concentrations
4 hours after the last dose with elevations persisting up to
16 hours after. The incidence of ephedrine use has been
shown to be high in bodybuilders (504), weightlifters (218),
and gym members (280).
Performance changes with ephedrine use are less clear.
Initial use of pseudoephedrine did not enhance running or
cycling performance (108,110,202,489), although one study
found greater peak power during cycling and muscle strength
(201). Studies examining ephedrine supplementation alone
have only shown limited ergogenic effects on performance
(50,256). However, a caffeine/ephedrine stack can result in
higher blood pressure, heart rate, blood glucose, minute
ventilation, insulin, free fatty acids, and lactate concentrations
during exercise (50,224) and result in greater increases in
power output, time to exhaustion (50,51), and faster 3.2 km
loaded run times (49).
Clenbuterol. Clenbuterol (i.e., Spiropent, Prontovent, Novegam, Clenasma, Broncoterol) is a b2 agonist used to treat
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asthma because it is a bronchodilator and has similar
hormonal, metabolic, cardiovascular, and sympathetic nervous system effects as stimulants. Clenbuterol is banned in
competition by WADA. However, athletes have used
clenbuterol because (a) it has been shown to increase muscle
hypertrophy and strength (more so than other b2 agonists)
and (b) it increases lipolysis (99,158,277,471). Clenbuterol has
been shown to enhance muscle strength and power (409)
and is usually stacked with other drugs. It has been used in
an ‘‘on/off’’ manner such that athletes will use for 2–3 weeks
and then discontinue use for 2–3 weeks at doses of ;60–140
mcgd21 (326). The half-life of clenbuterol is ;35 hours and it
accumulates with subsequent repeated doses. Approximately
97% of clenbuterol is removed from the body within 8 days
(334). Side effects of clenbuterol use include increased heart
rate, heart’s force of contraction, tremors, muscle cramps,
palpitations, insomnia, nervousness, and headaches (294).
Human Chorionic Gonadotropin (hCG). Human chorion
ganadotropin is a dimeric glycoprotein hormone found in
the placenta of women (226). Athletes use hCG because it
has been shown to stimulate the Leydig cells to produce
testosterone naturally (226). In men, hCG acts very similar to
LH, as it has specific target receptors on Leydig cells,
activation leads to activation of a cyclic adenosine monophosphate secondary messenger system, and stimulates
steroidogenesis (292). It has been shown that 3,000 IU of
hCG resulted in significant elevations in testosterone in
athletes (264). A 50% elevation in plasma testosterone level
was observed 2 hours after injection of 6,000 IU of hCG
(430). The response appears biphasic in that peak elevations
in plasma testosterone may be observed 3–4 days after hCG
administration (292). About 20–30% of hCG administered
is excreted in urine within 6 days (292). Often hCG is stacked
with androgens when athletes are cycling down in an
attempt to enable athletes to rejuvenate their own testicular
size and testosterone-producing capacity and to maintain
some of the anabolic effects associated with androgens.
Despite acute elevations in testosterone after 1 injection of
hCG in androgen users just coming off of a cycle (346), it
appears administration of hCG (5,000 IU) 3 times per week
for a few weeks may be needed to maintain normal
testosterone concentrations (347). In addition, use of hCG
to increase natural testosterone production has been used
to stabilize the T:E ratio (as epitestosterone increases) for
athletes doping with testosterone (292). Kicman et al. (291)
and Cowan et al. (123) have shown that a single-dose hCG
administration (5,000 IU) resulted in substantial elevations
in testosterone, yet no significant change in the T:E ratio.
Because hCG increases testosterone, several side effects with
testosterone or anabolic steroid use may also be seen with
hCG, especially at higher doses. Doses of 1,000–7,000 IU of
hCG injected every 5 days have been used by athletes in 3–4
week cycles, although others have used greater quantities for
cycles extending beyond 8 weeks (326).
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Site Enhancement Drugs. Site enhancement drugs are mostly
used by bodybuilders. These drugs, for example, Synthol,
Nolotil, Caverject, cause temporary muscle size increase
when injected locally (326). A drug formerly used, Esiclene,
was used as well because it led to swelling and inflammation
when injected locally. However, other drugs are now used by
bodybuilders for local site enhancement. Synthol is composed of medium-chain triglycerides, lidocaine, and benzyl
alcohol and is injected intramuscularly where it lodges
between the fascicles. Repeated injections lead to greater
volume within the muscles. Bodybuilders have been suggested
to inject 1–3 mL every day or every other day for 2–3 weeks
(326). Scientifically, little is known about these drugs and
potential side effects currently. Use of these drugs is unethical
and could lead to potential serious side effects.
Frequency of Androgen Use
The scientific evidence concerning the prevalence of the
nonmedical use of androgens within the U.S.A. is sorely
lacking. A recent report has indicated that since 1993 the
lifetime use of androgens for nonmedical reasons has
remained at a consistent 1% in the college student population
(348). Considering that there are more than 40 million
college graduates in this country (369), it can be crudely
extrapolated that more than 400,000 college graduates have
used androgens during their lifetime. In addition, a recent
survey has suggested that nearly half of all users of androgens
hold a college degree (114). Considering then that half do
not, it may be further extrapolated that more than 800,000
individuals in the U.S.A. have used androgens during their
lifetime. However, most surveys examining the nonmedical
use of androgens have focused on collegiate and adolescent
students and athletes. Information concerning adult use is
generally limited to surveys of individuals who are selfadministering androgens.
In the adult population of androgen users, the median age
of individuals using androgens is 29 years, with nearly half of
them holding at least a bachelors degree and more than 5% of
self-admitted users holding a terminal degree (e.g., JD, MD or
PhD) (114). Most adult users of androgens in the U.S.A. are
whites (88.5%) and employed as professionals with yearly
income exceeding that of the general population (114). The
primary reason for drug use among the general population of
androgen users appears to be related to increases in strength
and muscle mass and wanting to ‘‘look good’’ (114,246).
Other motivating reasons for drug use also include reduction
of body fat, improvement to mood, and attraction of sexual
partners. Interestingly, of the 1,955 androgen-using males
surveyed bodybuilding and sports performance were either
not motivation for androgen use or of little importance (114).
Although recent media reports have focused on performance-enhancing drug use in professional athletes and
youth, the majority of adults who self-administer androgens
for nonmedical purposes appear to be intelligent, economically stable, white men who are not competitive athletes.
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Based on media exposure, the underlying belief is that
the use of performance-enhancing drugs, specifically anabolic
steroids and GH, is rampant among professional athletes
today. Although 67% of the U.S. powerlifting team in 1995
was reported to have used anabolic steroids (520) and
anecdotal reports suggested that anabolic steroid use in the
NFL ranged between 50 and 90% of players during the 1970s
and 1980s (543), the available scientific evidence of the past
few years indicate that illegal performance-enhancing drug
use among competitive athletes is declining. In a survey of
almost 14,000 NCAA student athletes, the NCAA reported
that the number of collegiate athletes who self-admitted to
androgen use has declined over the past 12 years (14,368).
According to the survey, the number of collegiate athletes
who self-admitted to androgen use has decreased from 4.9%
in 1989 to 1.4% in 2001. These trends were apparent in all
sports including football, in which androgen use among those
athletes was reduced by approximately 50% during this same
period (14,368). Interestingly, the racial/ethnic differences
reported among the general population of androgen users
appear to become more balanced among collegiate athletes.
Androgen use among African-American collegiate athletes
(1.1%) appears to be as common as that seen in white student
athletes (1.1%) (213). Regardless, specific use patterns among
professional and Olympic caliber athletes remain a mystery
and unfortunately professional sport organizations within the
U.S.A. do not release any of their drug testing results to the
general public. Consequently, most information emanating
from professional sports has been based on innuendo and
hearsay.
A concern that first appeared on NCAA performanceenhancing drug surveys was the change in the age of initial
androgen use among collegiate athletes who self-admitted to
using these drugs. During the initial years of the survey, the
majority of college athletes using these banned drugs did so
toward the end of their college careers. Presumably, this
was to enhance their chances of playing at the next level (i.e.,
professional sports); however, the trend seen in recent
publications of the survey began to show a decrease in the
age of initial androgen use. It appears that more than 40% of
college athletes who admit to using androgens today appear to
first begin using these drugs in high school (368). Even more
disturbing were reports that androgens use was also beginning
to be seen in middle school students (175,478). However,
a recent study was unable to support these findings (246).
Examination of androgens use among the adolescent
population appears to be following the same trend seen in the
professional and collegiate athlete. Early studies examining
performance-enhancing drug use in adolescents reported
that androgen use at the secondary level ranged from 6% (91)
to 11% in males (274). During the past 10–15 years, the use
of androgens among adolescents appears to also be on the
decline with self-reported use ranging from 1.6 to 5.4%
(154,159,246,253,370,441,493). Studies showing a higher
incidence (.6% self-admitting) of use have specifically
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examined high school football players (478). However,
comparisons of androgen use among adolescent athletes
and nonathletes have been inconclusive. Although some
studies have indicated that there is no difference in androgen
use among adolescent athletes and nonathletes (154,370),
others have suggested that athletes tend to use these drugs
with greater frequency than nonathletes (441,493). The
pattern of performance-enhancing drug use among adolescents does appear to increase as students move through high
school, with a recent study indicating that 6% of high school
male twelfth graders admitted to using androgens (246). In
addition, androgen use among adolescents may be more
prevalent in the south (3.46%) vs. adolescents living in the
Midwest (3.0%), west (2.02%), or northeast (1.71%) (159). In
contrast to adults who self-administer androgens, adolescents
who use these drugs appear to have below-average academic
performance and are more apt to use recreational drugs
(159,359). Interestingly, recent research has suggested that
substance use, fighting, and sexual risk are better predictors of
adolescent androgen use than participation in competitive
sports (359).
One of the biggest changes in androgen use patterns has
become the prevalence seen in female athletes and adolescents. Males have generally been reported to have a 3- to
4-fold greater prevalence in androgen use than females, with
frequency of use patterns in females varying between 1.2 and
1.7% (159,160). However, in contrast to the declining use
reported among male adolescents, the early part of this
decade has resulted in several investigators reporting a greater
frequency of androgen use in female adolescents that have
ranged from 2.0% (359) to 2.9% (253). However, several
recent studies have indicated that this trend toward a greater
frequency in androgen use among female adolescents may
have been overstated or at least declining (154,246).
Results from recent studies do suggest a decline in
androgen use among collegiate athletes and adolescent
males. However, the earlier onset of initial anabolic steroid
use, a potentially greater prevalence in the female population,
and the frequency of use in the nonathletic population
indicate that the problem of androgens is becoming more
societal than segmental regarding specific population groups.
Medical Issues Associated with Androgen Use and Abuse
The surreptitious nature of androgen abuse has rendered it
difficult to conduct systematic investigations of the adverse
effects of androgens in athletes and recreational bodybuilders.
Consequently, these investigations have been sparse and
confounded by the enormous variability in the types of drugs
used; the dose, frequency, and duration of androgen use; the
age at initiation; and concurrent use of accessory drugs. The
veracity of self-reported drug use is always suspect.
It is remarkable that the frequency of serious adverse effects
associated with androgenic steroid use has been as low as it
has been reported; this has abetted the false perception that
these drugs are ‘‘not too dangerous’’ and contributed to
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a sense of complacency among regulatory agencies. Some of
this false sense of safety relates to the low frequency of adverse
effects observed with substantially lower doses of androgens
used in clinical trials than those used by athletes and
recreational bodybuilders. Although the highest dose of
testosterone enanthate used in clinical trials has been 600 mg
weekly, 60% of androgen users in a survey reported using
1,000 mg of testosterone or its equivalent (388). Furthermore,
25% of androgen users also used GH or insulin (388).
Table 5 lists the adverse events that have been reported in
association with androgen abuse, including mood and
psychiatric disorders (406); increased risk of suicidal or
homicidal death (389); deleterious changes in the cardiovascular risk factors, including a marked decrease in plasma HDL
cholesterol level (204,391) and changes in clotting factors (15);
suppression of the hypothalamic-pituitary-testicular axis and
spermatogenesis resulting in infertility; and increase in liver
enzymes (144,397,467). Individuals abusing androgens often
also concomitantly abuse other accessory drugs, including
stimulants, such as amphetamines and cocaine; these accessory
drugs may have serious adverse effects of their own. Also,
individuals who abuse androgens may engage in high-risk
behaviors that may increase the risks of HIV infection, injury, or
violence.
Androgen Abuse and Mortality. A number of deaths due to
unexpected coronary and cerebrovascular events have been
reported among androgen users (351,531), but these reports
are largely anecdotal and they do not establish a causative
role of androgen use in these deaths. There have been
remarkably few systematic investigations of the mortality and
health consequences of androgen use by athletes. Parssinen
et al. (389) investigated mortality and underlying causes of
mortality among 62 powerlifters who had achieved the top 5
positions in weightlifting competitions in the 82.5–125.0 kg
weight categories during the 1977–1982 period. The
reference group included age-matched individuals from the
general population. Thirteen percent of powerlifters and
3% of the age-matched control group died during this period.
Suicides, myocardial infarction, hepatic coma. and non–Hodgkin’s lymphoma contributed to deaths among powerlifters. Thus, in this relatively small series, the risk of death
among the powerlifters was 4.6 times higher than that in the
control population. In another study, the median age of death
among androgen users who died and were autopsied was
24.5 years (398); this remarkably young age of death among
androgen users is even lower than that for heroin or
amphetamine users (398). Another study of patient records in
Sweden (399) also reported substantially higher standardized
mortality ratios for subjects who were androgen users than
for those who were not, indicating increased risk of
premature death among androgen users.
Thiblin et al. (498) investigated the cause and manner
of death among 34 androgen users whose deaths were
investigated medicolegally: 32% committed suicide, 26%
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of atherosclerosis, increase the
risk of thrombosis through
TABLE 5. Potential adverse effects associated with androgen use.*
their effects on clotting factors
and platelets, induce vasospasm
Potential adverse effects of high doses of androgens
through their effects on vascuBehavioral and psychiatric side effects
Increased risk of suicidal and homicidal death
lar nitric oxide, or induce
Depression
myocardial injury because of
Hypomania and mania
their direct effects on myocarIncreased risk of the use of stimulants and psychoactive drugs, and
dial cells (180,349,351).
accessories such as hCG, clomiphene, and aromatase inhibitors
The effects of androgens on
Cardiovascular complications
Lowering of HDL cholesterol
plasma lipids and lipoproteins
Increased LDL cholesterol
depend on the dose, the route
Sudden cardiac death
of administration (oral or parMyocardial hypertrophy and dysfunction
enteral), and whether the anProlonged suppression of hypothalamic-pituitary-testicular axis
drogen is aromatizable or not
Hepatic dysfunction, neoplasms, and peliosis hepatic
Gynecomastia
(29,47,58,75,151,255,265,289,
Potential adverse effects of intramuscular injections
463,464,529,545).
Parenteral
Local infection and abscess
administration of replacement
Systemic infection, including HIV and hepatitis C virus
doses of testosterone is associUnique adverse effects associated with androgen use in women
ated with a small decrease in
Hirsutism
Clitoral enlargement
plasma HDL cholesterol levels
Change of body habitus, including widening of upper body torso
and little or no effect on total
Breast atrophy
cholesterol, low-density lipoMenstrual irregularity
protein (LDL) cholesterol, and
Unique adverse effects associated with androgen use in children
triglyceride levels (58,463,529),
Premature epiphyseal fusion and growth retardation
Premature virilization in boys and masculinization in girls
but supraphysiologic doses of
Increased risk of unhealthy behaviors
testosterone, even when adminUse of alcohol, tobacco, and other drugs
istered parenterally, markedly
Less frequent seatbelt use
decrease HDL cholesterol levels
More sexual activity
(63,456). In contrast, orally adAntisocial behavior
Declining academic performance
ministered, 17-alpha-alkylated,
More fasting, vomiting, diet pill, and laxative use by young girls
nonaromatizable
androgens
produce
greater
reductions
in
*hCG = human chorionic gonadotropin; HDL = high-density lipoprotein; LDL = low-density
plasma
HDL
cholesterol
levels
lipoprotein; HIV = human immunodeficiency virus.
and greater increments in LDL
cholesterol than parenterally
administered testosterone (265).
were victims of homicide, and 35% of deaths were deemed
Increases in left ventricular mass have been reported among
accidental (498). Use of multiple drugs, cardiac causes, and
users of androgenic steroids (143,144,284,288,351,392,488).
impulsive and uncontrolled violent behaviors were among
As many androgen users are powerlifters who engage in
the contributory causes of accidental deaths (498).
high-intensity resistance training that can induce left ventriA majority of androgen users who die prematurely also
cular hypertrophy, it is not clear whether the left ventricular
have used other psychoactive drugs (398). Androgen users
hypertrophy reported in powerlifters is a consequence of
who commit suicide have been noted to express depressive or
resistance training or androgen use or both (392). Although
hypomania-like symptoms or to have committed acts of
we do not know for sure whether the increase in left
violence or experienced interpersonal difficulties at work or in
ventricular mass observed in androgen users is beneficial or
personal life in the period immediately preceding suicide (499).
deleterious, a study of left ventricular function in power
athletes who were using androgens found significant impairment of both systolic and diastolic function (140,145). In
Cardiovascular Effects of Androgens. Androgens affect the
another study, Urhausen et al. (507) used echocardiography
lipoprotein profile, myocardial mass and function, cardiac
to assess left ventricular mass and wall thickness among male
remodeling, and the risk of thrombosis (75,143,284,340,351,
powerlifters and bodybuilders who were currently using
372,431,488). Several potential mechanisms have been
androgens, ex-users who had not used androgens for more
proposed to explain the adverse cardiovascular effects of
than 12 months, and weightlifters who had never used
androgens (351). High doses of androgens may induce
androgens. Current androgen users had higher left
a proatherogenic dyslipidemia and thereby increase the risk
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ventricular muscle mass than nonusers or previous users
(507). The E:A ratio (a measure of the peak velocity of
the early rapid filling [E-wave] and filling during atrial systole
[A-wave]) is reduced in powerlifters using androgens,
suggesting altered diastolic function (479). Large doses of
androgens may increase the risk of heart failure and fibrosis
(143,144,288,351,372,392,488). Myocardial tissue of powerlifters using large doses of androgens is infiltrated with fibrous
tissue and fat droplets (372).
There are several case reports of sudden deaths among
power athletes who were abusing androgens (143,144,150,
185,186,231,333,488). Many of the sudden deaths have been
associated with myocardial infarction. Some of the myocardial infarctions were deemed nonthrombotic, leading to
speculation that androgens might induce coronary vasospasm (392). These case reports are largely anecdotal, and
a causative relationship between androgen use and the risk of
sudden death is far from established. Power athletes using
androgens often have short QT intervals but increased QT
dispersion in contrast to endurance athletes with similar left
ventricular mass who have long QT intervals but do not
have increased QT dispersion (479). QT interval dispersion
has been used as a noninvasive marker of susceptibility
to arrhythmias (411); we do not know whether this
predisposes powerlifters who abuse large doses of androgens
to ventricular arrhythmias.
Psychiatric and Behavioral Effects of Androgens in Athletes.
Anecdotal reports of rage reaction in androgen users, referred
to as ‘‘roid rage,’’ have attracted a great deal of media
attention. However, placebo-controlled trials of testosterone
have shown inconsistent changes in anger scores or measures
of aggressive behaviors (129,303,407,487,503,541). Several
factors may have contributed to this inconsistency of results
across trials. The instruments used to measure aggressive
behavior have varied across trials, and it is possible that the
self-reporting questionnaires did not have sufficient sensitivity to detect small, but significant, changes in aggression.
Differences in weight training and related practices; concurrent use of other substances, such as alcohol, psychoactive
drugs, and dietary supplements; and preexisting personality
or psychiatric disorders are important confounders in interpretation of data related to behavioral effects of androgens
(30). None of the controlled trials of testosterone have
demonstrated significant change in aggression at physiologic
replacement doses of testosterone. In fact, testosterone
replacement in healthy androgen-deficient men has been
reported to improve positive aspects of mood and attenuate
negative aspects of mood (522). It is notable that only a small
number of subjects (less than 5%) in controlled trials have
demonstrated marked increases in aggression measures, and
only with the use of supraphysiologic doses of testosterone,
a majority of participants show little or no change (129,303,
407,487,503,543). It is possible that high doses of androgens
might provoke rage reactions in a subset of individuals with
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preexisting psychopathology. Indeed, aggressive individuals—
perhaps those with certain personality disorders—may be
more prone to abuse androgens. In a survey, more AAS users
than controls had worked as doormen or bouncers (357).
Among certain groups of criminals, the risk of having been
convicted of a weapon offense was higher for androgen users
than for nonusers (295). Anecdotal reports suggest that even
among individuals without histories of psychiatric disorders
or antisocial personality disorder or violence, the use of high
doses of androgens might predispose men to violent or
homicidal behavior (405).
It is possible that because of strong societal constraints
against aggressive behavior, the self-reporting instruments fail
to capture changes in the participant’s behavior. However,
when confronted with a provocative challenge, the individuals receiving high doses of androgens might display unexpectedly high level of aggression and rage. This hypothesis
was tested by Kouri et al. (303) using an innovative study
design. These investigators reported that administration of
supraphysiologic doses (600 mg weekly) of testosterone
enanthate to healthy young men was associated with a
significant increase in aggressive responses than placebo
administration. During the investigation, healthy young
men randomly received either placebo or graded doses of
testosterone. At baseline and at the end of the treatment
period, the participants were asked to play a game against
a fictitious opponent; the participants were unaware that
the opponent was fictitious. The participants had the choice
of pressing button A to receive a financial reward or button
B that would take money away from a fictitious opponent
(aggressive responding). The objective of the game was to
achieve the highest monetary gain and the best strategy to
achieve that goal was to keep on pressing button A.
Remarkably, individuals receiving supraphysiologic doses
(600 mg weekly) of testosterone enanthate opted to select
button B (to punish the fictitious opponent) with greater
frequency and thus had higher scores on aggressive
responding than those associated with no testosterone or
lower doses of testosterone. Thus, when provoked by a
hostile situation, the level of aggressive response was higher
when individuals were receiving high doses of testosterone
than when they were receiving placebo or lower doses of
testosterone enanthate.
Steroid users experience high frequency of mood disorders, such as mania, hypomania, or major depression,
during androgen use (339,406,408,509). Major depression
has been reported during periods of androgen use but is
more often observed during withdrawal of high-dose
androgen use (339,406,509). A high proportion of
women athletes using high doses of androgens report
symptoms of hypomania and depression, rigid dietary
practices, and dissatisfaction and preoccupation with their
physique (219).
Kanayama et al. (279) have reported a high frequency of
prior androgen abuse among male substance abusers. In a
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sample of 223 male substance abusers, who were hospitalized
for the treatment of alcohol, cocaine, and opioid dependence,
13% reported prior androgen use, leading those investigators
to speculate that AAS use may predispose some individuals
to substance abuse.
Liver Toxicity. The elevations of liver enzymes, cholestatic
jaundice, hepatic neoplasms, and peliosis hepatis have been
reported mostly with the use of oral 17-alpha alkylated
androgenic steroids (94,146,301,390,466,467) but not with
parenterally administered testosterone or its esters (95). Most
cases of hepatic neoplasms in association with androgen use
have occurred in patients with myelodysplastic syndromes
(366). The risk of hepatic dysfunction during androgen
administration probably has probably been overstated
(145,247), being extremely uncommon in individuals receiving parenteral androgens. Furthermore, it is not clear
whether elevations in aspartate aminotransferase and alanine
aminotransferase during androgen administrations are the
result of liver dysfunction or of muscle injury resulting
from strength training or a direct transcriptional effect of
androgens on AST gene (145,397).
The Suppression of Hypothalamic-Pituitary-Testicular Axis.
Androgen administration suppresses endogenous pituitary
LH and follicle-stimulating hormone (FSH) secretion and
indirectly testicular testosterone and sperm production
(200,337). Because of predictable suppression of the hypothalamic-pituitary-testicular axis, men using androgens may
experience subfertility or infertility (327). Indeed, androgens,
alone or in combination with other gonadotropin inhibitors,
are being investigated as potential male contraceptives (538).
After discontinuation of the exogenously administered
androgen, the recovery of the hypothalamic-pituitary axis
may take weeks to months, depending on the dose and
duration of prior androgen use (88–90,262). After discontinuation of exogenous androgen use, circulating testosterone
concentrations may fall to very low levels as the effects of
exogenous testosterone wear off and the endogenous axis
has yet not recovered. During this period, the users may
experience troublesome symptoms of androgen deficiency,
including loss of sexual desire and function, depressed mood,
and hot flushes. Some patients who find these withdrawal
symptoms difficult to tolerate may revert back to using
androgens or may seek recourse to other psychoactive drugs,
thus perpetuating the vicious cycle of abuse, withdrawal
symptoms, and dependence (88–90). Others may resort to
off-label use of aromatase inhibitors or hCG obtained illicitly
based on the folklore widely prevalent in the gymnasia that
these agents can accelerate the recovery of the hypothalamic-pituitary-testicular axis, although there is no evidence
to support this premise. The long-term suppression of the
hypothalamic-pituitary-testicular axis with its attendant risk
of dependence and continued use of androgenic steroids are
serious complications of androgenic steroid use that have not
been widely appreciated.
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Gynecomastia. Breast tenderness and breast enlargement are
frequently associated with the use of aromatizable androgenic
steroids (28,81,139,484). The exact prevalence of breast
enlargement in androgen users is unknown, but prevalence
rates as high as 54% have been reported (28,139,406,484). In
a series of 63 patients referred for surgical correction of
gynecomastia, 20 men had used anabolic steroids (28). It is
not uncommon for athletes to use an aromatase inhibitor or
an estrogen antagonist in combination with androgenic
steroids to prevent breast enlargement.
Androgen Abuse and Insulin Resistance. The effects of
testosterone on insulin sensitivity are biphasic and depend
on the dose. In cross-sectional studies, low testosterone levels
are associated with increased risk of insulin resistance and
type 2 diabetes mellitus (132,164,220,221,402,403). Testosterone replacement in castrated rats and hypogonadal men
improves measures of insulin sensitivity (249); however,
supraphysiologic doses of testosterone render castrated rats
insulin resistant (249). Orally administered 17-alpha alkylated
androgens also have been associated with insulin resistance
and glucose intolerance (115).
Risks Associated With Intramuscular Injections of Androgens. The
majority of androgen users administer androgens by intramuscular route; 13% of those who use intramuscular
injections reported unsafe injection practices (388). Self-administration of intramuscular injections increases the risk
of infection, muscle abscess, and even sepsis (172). Transmission of HIV infection and hepatitis has been reported
among parenteral androgen users, presumably because of
needle sharing or the use of improperly sterilized needles and
syringes.
Risks Associated With Excessive Muscle Hypertrophy. Excessive
muscle hypertrophy without commensurate adaptations in
the associated tendons and connective tissues may predispose
athletes using androgens to the risk of tendon injury and
rupture and unusual stress on joints (173).
Risks Associated With the Use of Accessory Drugs. It has been
reported that 90% of androgen users abuse additional drugs
(171,388). Almost one-quarter of androgen users also take
hGH or insulin (388). Some of these additional drugs of
abuse, such as cocaine, amphetamine, and ephedra, may be
associated with potentially serious medical complications.
Other Concerns. There are concerns about potential effects
of androgens on the risk of prostate disease (57,59,61). The
long-term effects of supraphysiologic doses of androgens on
the risk of prostate cancer, benign prostatic hypertrophy, and
lower urinary tract symptoms are unknown.
Medical Issues Associated With Androgen Use Among Women.
Women taking androgens may undergo masculinization
and experience hirsutism, deepening of voice, enlargement
of clitoris, widening of upper torso, decreased breast size,
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menstrual irregularities, and male pattern baldness (141,390).
Some of these adverse effects may not be reversible. In
addition, epidemiologic studies have reported an association
of elevated testosterone concentrations in women with increased risk of insulin resistance and diabetes mellitus (149).
Medical Issues Associated with Androgen Use Among Children
and Adolescents. In addition to the adverse effects observed in
adults, adolescents may be susceptible to some unique adverse
effects of androgens (103,425,514). Pre- or peripubertal boys
and girls may undergo premature epiphyseal fusion, which
may result in reduced adult height (103,514). Androgen
abuse by children is associated with other unhealthy
behaviors, such as use of alcohol, tobacco, and other drugs;
less frequent seat belt use; more sexual activity; antisocial
behavior; declining academic performance; and more fasting,
vomiting, diet pill, and laxative use by young girls (514). Boys
may undergo premature or more accelerated pubertal
changes, whereas girls may experience virilization.
Testing of Androgens
Current Analytical Methods of Detection. Relative to the various
analytical method of androgen detection, current detection
techniques suffer from an extensive sample pretreatment
and thus from low sample throughput. Developing new test
methods, which requires the preparation of suitable reference
compounds, will allow modern drug testing techniques to
be more widely and more effectively utilized. The availability
of numerous synthetic steroids and recombinant peptide
hormones has made testing an analytical challenge. Recent
advances in mass spectrometry have provided an opportunity
to decrease detection by utilizing gas chromatography (GC)
coupled to high-resolution mass spectrometry (HRMS). A
further improvement may be seen with GC-MS/MS and
quadrupole ion traps. Electrospray high-performance liquid
chromatography (HPLC) coupled to high-resolution MS
(HPLC-MS) has also been applied to the detection and
confirmation of peptide hormones in urine. The ability to
detect subtle differences in oligosaccharide structure may
provide a way to detect abuse of recombinant glycoproteins.
Simply decreasing detection limits is not enough; new
technology also allows development of a foundation on
which to base interpretation. Application of HPLC-MS/MS
has allowed direct measurement of steroid conjugates in
urine (1,2). The relative importance of sulfate, glucuronide,
and other conjugates and metabolites of testosterone and
epitestosterone can now be assessed (2). A 2-stage procedure,
the liquid chromatography-mass spectrometry (LC-MS)
technique, will become a much more effective and
straightforward testing method, thus offering additional
reliability on doping testing.
In light of this, various athletic commissions around the
world have begun to analytically detect androgens by way of
the steroid glucuronides-liquid chromatography/mass spectrometry. Once androgens have been ingested, the body
starts to convert them so that they can be more easily
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discharged or eliminated as bodily waste matter. The main
androgen derivatives found in urine samples are combined
with glucuronic acid. Testing for exogenous androgen use is
carried out on a sample of an athlete’s urine. It is analyzed
using a 2-stage LC-MS (2). The components of the urine
sample are first separated using liquid chromatography, and
then the presence of androgens is detected using mass
spectrometry (2). The results can be quantified by comparison with those obtained from a series of standard solutions
with known concentrations of androgen glucuronides (133).
These androgen derivatives are complex molecules, and
because several reaction steps are involved as well as the
purity required, their preparation takes a long time and so the
substances are expensive. Furthermore, based on recent
change in the threshold for androgen detection where the
T:E ratio is now at 4:1 rather than 6:1, methods of detection
must now employ the capability of greater sensitivity. More
recent advances in MS have provided this capability.
High-Resolution Mass Spectrometry for Low-Level Androgen
Detection. Accredited laboratories are required to detect
certain androgens at levels of 2 ngmL21 or lower. Detection
at such low levels requires HRMS or tandem mass
spectrometry (MS/MS), both of which are more sensitive
than conventional mass spectrometry. A mass spectrometer
bombards a chemical substance with an electron beam to
produce charged particles (ions) that are separated and
detected based on their mass to charge ratio. By tuning the
instrument to characteristic molecular fragments, drugs can
be detected sensitively with little interference from other
compounds, which produce different fragments. Highresolution mass spectrometry (HRMS) is better able to
distinguish between fragments of interest and those arising
from other chemical compounds in the urine and allows
detection of steroid residues in urine at levels 5–10 times
lower than was possible using the conventional technique. In
MS/MS, the fragments from the initial ionization are again
bombarded and mass analyzed. New purification techniques
have also been introduced, which have been developed as
a complement to sensitive detection techniques to increase
the sensitivity of drug detection. A method using HPLC
to prepare clean extracts for most androgens and their
metabolites has been developed and validated. This methodology is now in routine use. An instrument capable of
performing MS/MS analysis can complement HRMS, in
that MS/MS can give a definitive result with some samples
that prove difficult to confirm by HRMS. The main
advantage of these sensitive techniques is that androgens
can be detected for a much longer time after administration;
androgen use can now be identified for weeks longer than
was possible a few years ago.
Isotope Ratio Mass Spectrometry for Androgen Detection. The
usual technique for detection of androgen use is to compare
its concentration with that of a related compound, epitestosterone, in the urine (T:E ratio). A T:E ratio greater than 4
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may indicate androgen use. However, there is a wide variation
in natural T:E ratios between individuals, so that in some
cases the T:E ratio may be above 6 even though the individual
has not taken androgens, whereas in others the value may
stay below 4 despite androgen use. The natural T:E ratio,
measured over a period, tends to be constant, and any
variation in an individual’s T:E ratio over time may indicate
androgen use. One technique that can complement the
measurement of T:E ratios is the use of GC coupled to IRMS
(GC-IRMS). This technique utilizes the fact that natural and
administered substances, such as testosterone, have small but
measurable differences in the ratio of carbon-12 to carbon-13
isotopes (C12:C13 ratio) (because of the different pathways
used in the preparation of the natural and synthetic forms). By
measuring the C12:C13 ratio of androgens detected in urine,
GC-IRMS can distinguish exogenously administered androgens (synthetic form) from endogenously synthesized
androgens (natural form). This provides an ability to identify
androgen abuse in cases that would have previously gone
undetected. The application of this technique is not simple
because the instrumentation is expensive and requires high
precision, and larger sample sizes are needed, which increases
the amount of sample preparation required before analysis.
Criteria for Detection. The primary biological fluid used for
detecting androgen use has typically been urine. Urinary
analysis has been successful for the majority of androgens,
especially the synthetic varieties that have specific structures
easily identifiable by GC-MS. However, the detection of
androgens is not absolute and does involve limitations.
Methods for detecting the use of androgens depend on
alterations in the normal urinary testosterone (T) level. Much
work has been done with the intent of determining
appropriate urinary markers indicative of androgen use.
Traditionally, the ratio of androgen glucuronides to epitestosterone (E; 17-a-hydroxy-4-androstene-3-one) has been
used, as was adopted by the Medical Commission of the IOC,
with a cutoff point of $6 being the primary indicator of
androgen self-administration (386) compared with the
normal urinary T:E ratio for healthy athletes not using
androgens being approximately 1 (293). The increase of the
T:E ratio after high-dose androgen use results from increased
T excretion and a subsequent decrease in E output (134).
Even so, however, some athletes have produced false-positive results revealing T:E ratios $ 6 with subsequent
verification that no androgens had been administered (133).
It has been suggested that this problem could be attenuated
by taking into account the sulfate excretions of epitestosterone in the T:E ratio, thereby suggesting that the relevant
threshold of the T:E ratio being 3 would be a more sensitive
maker of covert androgen use (134).
World Anti-Doping Agency defines as suspect a T:E ratio
of 4:1. This is more than 6 SDs for the expected norm of 1:1 in
the general population. Using a smaller ratio, however, would
be impractical. For example, using publicly available data,
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only 3 of nearly 500 cases since 2004 where the T:E ratio
was between 4:1 and 6:1 resulted in a confirmed adverse
analytical finding under the WADA system. The preliminary
GC/MS screen for testosterone in urine is known as the T:E
ratio test. T stands for testosterone; E, epitestosterone,
a natural, inactive isomer of testosterone. In most individuals,
the T:E ratio is ;1:1. A T:E ratio of 4:1 may indicate the
presence of synthetic testosterone. World Anti-Doping
Agency has established that a T:E ratio of $4:1 is the
threshold that triggers further testing of an athlete’s sample.
Upon collection, each sample from an athlete is split into 2
vials, A and B, and sample A is tested first. The T:E test has 2
parts: a screening phase and a confirmation phase. T and E
are identified by the main MS fragment ions produced from
their respective trimethylsilyl derivatives in the screening phase.
Once a chromatogram is produced, the T:E ratio is estimated
on the basis of the peak area ratio. If the T:E ratio is $4:1, then
a GC/MS confirmation test is performed. Two new aliquots,
one that is hydrolyzed and one that is not, are prepared for this
test. The aliquot without hydrolysis measures free T and E to
verify that the urine sample did not break down.
Interestingly, because the secretion of testosterone is under
the control of LH, it has been suggested that the urinary T:LH
ratio could conceivably be a useful marker for detecting
androgen use (87). High-dose androgen use is known to result
in dose-dependent suppression of both serum and urinary LH
(291), based on the premise that LH excretion is typically
reduced to a lesser extent than the decrease in both epitestosterone and testosterone conjugates. Therefore, increased serum
and urinary T:LH ratios in the presence of a normal T:E ratio
may be indicative of androgen use. In light of this, it has been
shown that a urinary T:LH ratio of $30 is a more sensitive
marker of androgen use than the urinary T:E ratio of $6, and
remains sensitive for twice as long as urinary T:E (396).
Effect of Genotype on Testing Results. Doping tests for the past
10 years have demonstrated that Asian individuals excrete
a reduced amount of testosterone glucuronide (136,387),
which may result in an increased risk of a false-negative drug
test in this ethnic group. This was part of the motivation for
changing the upper normal limit of 6 to 4 for the T:E ratio.
Recent studies have suggested that a deletion polymorphism
in the gene coding for uridine diphospho-glucuronyl transferase 2B17 (UGT2B17), the principle enzyme for the
glucuronidation of androgens and their metabolites, is
associated with a T:E ratio below 0.4 (259). This was seen
to be more common in Asian than in a white population.
A recent study by Schulze et al. (440) examined 55 male
subjects who were genotyped for the UGT2B17 deletion. Of
these subjects, 31% were homozygous for the gene deletion,
44% were heterozygous for the gene deletion, and 25% had 2
copies of the gene. Subjects had originated from different
ethnicities. After a single injection of 500 mg of testosterone
enanthate, urine samples were collected for 15 days. Results
demonstrated that the rate of increase in testosterone
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glucuronide excretion was highly dependent on the genotype
of UGT2B17. Forty percent of the subjects who were
homozygous for the gene deletion never reached the T:E
cutoff of 4 during the 15 days of the study. Interestingly, in the
group that had both copies of the gene, 14% of the individuals
had baseline T:E ratios above 4, resulting in a false-positive
test. However, by changing the ratio to 1.0 in the homozygous group and to 6.0 in the group that had both copies of
the gene, the sensitivity of the test increases to 100% within
6 days from injection. Thus consideration of the genetic
variation of testosterone glucuronidation enzymes appears to
be important in developing appropriate doping tests.
Legal Issues Associated With Androgens
Although androgens have always required a physician’s
prescription for use, it was not always listed as a controlled
substance. However, as a result of mounting pressure related
to androgen use among American adolescents, the U.S.
Congress in 1990 amended the controlled substances act to
include androgens. This was known as the Anabolic Steroid
Control Act. The passing of this law reclassified androgens
as a schedule III substance. The impact of this was to make it
a crime to use these drugs for nonmedical purposes. Other
schedule III substances include weak opioids such as codeine
and Vicodin, barbiturates, amphetamines, and methamphetamines. By 2004, an amended version of the Anabolic Steroid
Control Act was passed that modified the definition of
androgens to include 26 additional compounds that comprised designer androgens, such as THG, and prohormones,
such as androstenedione.
The simple possession of any schedule III substance
including androgens is punishable by up to a year in prison
and/or a fine of $1,000. However, if the person who is caught
in possession of androgens has a previous conviction for drug
possession or another crime they will be imprisoned for at
least 15 days and up to 2 years with a minimum fine of $2,500.
A third conviction for possession will require imprisonment
for at least 90 days but not more than 3 years with a minimum
fine of $5,000. Selling anabolic steroids or possessing
androgens with intent to sell is a federal felony offense. First
conviction is punishable by up to 5 years in prison and/or
a $250,000 fine. A second conviction for distribution of
androgens may result in a prison sentence of up to 10 years
with fines not exceeding $500,000.
Conviction of androgen possession or distribution results
in not only potential prison time and/or fine but may also
jeopardize future employment opportunities. If the convicted
person holds a license for employment, such as medical and
allied health professionals, a conviction may result in a loss of
licensure. In addition, students convicted of possession or
distribution of schedule III substances may forfeit their rights
to financial aid and other benefits. Clearly, users of illegal
performance-enhancing drugs face significant risk for jail
time, fines, and jeopardize both present and future employment opportunities.
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Direction of Future Research
The efficacy of androgen treatment in muscle wasting
diseases has clearly been established. Continued research is
needed to further identify clinical populations that may
benefit from androgen therapy and combined exercise and
androgen treatments. In addition, identification of dosingrelated adverse events will provide a clearer understanding of
risk vs. reward regarding androgen treatment. Research on
selective AR modulation is very promising in this regard and
needs to be further elucidated.
Regarding androgen use in healthy athletic populations,
there is a need to increase research on maximizing performance gains through modulations in nutritional and exercise
regimens and when appropriate the inclusion of legal and
efficacious supplements. Providing viable alternatives to
athletes contemplating illegal drug use could potentially
reduce the number of athletes who are willing to take
such chances. In addition, further understanding of the
effect of changes in androgen profiles in athletes during the
competitive season is warranted. Although anabolic and
catabolic hormonal changes have been well documented
during various exercise stresses, there are only limited data
available concerning changes in competitive athletes during
a season of training and competition. Furthermore, investigations designed to study the effect of various recovery
methods, nutritional interventions, sport supplements, and
exercise routines on endocrine function in such athletes would
provide valuable information to coaches and athletes regarding
potential methods used to promote an optimal training environment and maximize athletic performance.
GROWTH HORMONE
The purpose of this overview of GH is presented for the most
part beyond what is found in classical endocrine textbook
aspect of GH physiology. It is vital to gain an understanding of
what lies beyond the typical physiology and is related to the
use of GH for physical development and enhancement of
sport performance.
What Is Growth Hormone?
Growth hormone also called somatotropin in the older
literature is a pleiotropic peptide hormone synthesized,
stored, and released from the anterior pituitary gland (353).
The most commonly measured form of GH is the 191 amino
acid isoform. This 22-kDa isoform contains numerous
cleavage sites and can be structurally distinguished via its
positioning of cysteine residues that are responsible for its
internal disulfide loop and smaller disulfide loop located at
the C-terminus. Other variants include a 20-kDa form
produced by the gene deletion for 14 amino acids and many
other post-translational isoforms of unknown physiological
significance (42). The GH produced for commercial use is
100% the 22-kDa isoform. This is important information for
the detection of hGH abuse.
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At present, detection of hGH abuse has not been validated,
and this provides the primary motivation for use by athletes.
In addition, the measurement and elucidation of its biological
properties are complex, as hGH does not exist as a single,
molecular species. It has been suggested that more than 100
different hGH isoforms exist, all arising from one of 2 genes
(41,43). Post-translational modifications include acetylation,
deamination, and hetero- and homo-oligomerization
(43,320). The ability to form oligomers via either noncovalent or peptide (cystine) bonds may serve to increase the
half-life of the peptide in circulation or may have undiscovered biological properties, such as competitive binding
to the GH receptor. Dimeric hGH appears to be the most
abundant of the post-translationally modified products,
although oligomers up to pentameric GH have been
reported. Homo- and hetero-oligomers have been described
for the 22- and 20-kDa isoforms. Of particular interest is that
small proteolytic fragments and large aggregates are also
formed (43). The variable nature of these GH isoforms exists
in circulation and encompasses a wide range of molecular
weights (42). Thus, understanding the impact of ergogenic
use of GH as an anabolic agent is likely complex.
Mediation of GH effects occurs with its interaction with
the GH receptor. The GH receptor is a 70-kDa class I
cytokine/hemapoietin superfamily protein (319). It is
composed of 2 complexes that interact with the GH ligand
in a sequential manner to dimerize. Intracellular signaling
then occurs through a phosphorylation cascade via the
JAK/STAT pathway. The GH receptor exists in abundance
in many tissues, including the liver, muscle, and adipose
tissue. However, the GH receptor may not be specific to all
the GH variants (208,251). For instance, the tibial line
receptors, used in a bioassay, do not seem to interact strongly
with the 22-kDa monomer (208,251).
What Is the Physiological Role of Growth Hormone?
Its physiological role is linear growth in children, to promote
anabolic (tissue building) metabolism, and to alter body
composition as part of this anabolic role. Growth hormone
actions include the hepatic and local synthesis and release
of its main mediator, IGF-1. Its growth-promoting effects
include longitudinal bone growth by actions at the epiphysis
and the differentiation of the osteoblasts (420). It shares some
of these roles with IGF-1, meaning that the direct effect of
GH and/or local production of IGF-1 are both required for
optimal linear growth.
The release of GH is stimulated by growth hormone–
releasing hormone (GHRH) and is inhibited by somatostatin,
both hypothalamic hormones. However, there are many
other factors that affect GH regulation, most of which use
these hypothalamic hormones as a common path. Stimuli
to GH release include deep sleep; exercise; stress including
heat; hypoglycemia; nutritional intake; some amino acids (see
below); some pharmacologic agents, including clonidine, L DOPA, estrogens, and androgens (through an estrogen-
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dependent mechanism, especially in adolescents). Inhibitory
influences include obesity, ingesting a carbohydrate-rich diet,
and several pharmacologic agents, for example, beta-2
adrenergic agonists. The release of GH from the anterior
pituitary is pulsatile, meaning that its release is not constant but occurs in bursts (236,251) The largest peak GH
secretion occurs about an hour after the onset of sleep, with
subsequent smaller peaks occurring during the rest of the
sleep period (374).
Its major metabolic effects can be deduced from the
alterations in GH-deficient subjects—the reduction of lean
body mass, an increase in body fat, and a reduction in bone
mineral density. Administering hGH may reverse many of
these alterations (see below); however, it is not quite so simple
in that hGH has different acute effects depending on the
time after natural secretion or exogenous administration. It is
insulin-like in the first minutes, but then becomes diabetogenic (anti-insulin) at the liver and at peripheral sites several
hours after administration. Glucose utilization is decreased,
lipolysis is increased, and the tissues are refractory to the acute
insulin-like effects for several hours. Its direct actions include
amino acid transport in muscle leading to protein synthesis
and an increase in nitrogen balance, increased fat mobilization
through lipolysis (increased triglyceride hydrolysis to free
fatty acids and glycerol and reduction in fatty acid reesterification), and an augmentation of lipid oxidation.
Clinically these effects can be noted in the longer term by
a decrease in body fat and a decrease in the adipopcyte size
and lipid content.
The outcome of GH therapy in GH-deficient adults may
be an increase in FFM, both body cell mass (muscle), total
body water, especially the extracellular compartment, and
a decrease in body fat with redistribution from central to
peripheral stores (242).
Growth hormone has numerous functions in the organism,
including growth and development, metabolism, bone health,
hydration status, and cardiovascular function. The diverse
multitude of functions would appear to imply that more than
one form of GH (i.e., molecular variants) may be necessary to
mediate all these functions. However, for the purposes of this
review, the focus will be on the effects of hGH on protein
synthesis in muscle, as heavy resistance training is primarily
focused on this target tissue for development. In fact,
understanding the interactions of hGH with other anabolic
hormone signals is vital because it is unlikely that athletes use
hGH alone. As noted previously, it is likely that GH and
anabolic steroids are taken concurrently. Figure 6 depicts the
role of GH signaling in response to resistance exercise and
also the associated influence of other anabolic hormones,
which are commonly associated with anabolic drug use.
The effect of hGH on muscle hypertrophy appears to lie
in its ability to indirectly stimulate the mammalian target
of rapomyosin (mTOR) pathway via dimerization with its
receptor and subsequently activating the phosphorylation
cascade of the JAK/STAT pathway. The mTOR pathway
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has direct control over several components of translation in
protein synthesis via its downstream effectors, ribosomal S6
kinase 1 (S6K), eukaryotic initiation factor-I 4E binding
protein-1 (eIF 4E-IGFBP-1), and elongation factor 2 kinase
(eEF2) (198,232,338).
Hayashi and Proud (232) reported that GH also stimulates dephosphorylation of eEF2 and activates S6K, thus
playing a role in translation, initiation, and elongation of the
proteins synthesized. These downstream effects are thought to
be a result of the GH-mediated stimulation of phosphatidylinositol 3-kinase and protein kinase B (PKB, also called
AKT) (232).
The mTOR pathway can also be activated by the
extracellular ligand–regulated kinase (ERK) pathway via
phosphorylation of the JAK/STAT pathway subsequent to
GH ligand binding to the GH receptor in disease states such
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as cancer and likely occurs during musculoskeletal protein
synthesis (19,335,426) A further role of GH in skeletal muscle
growth is related to its ability to increase myonuclear number
and to facilitate the fusion of myoblasts with myotubes (469).
It has also been reported that hGH has stimulating role
in the incorporation of ingested amino acids on protein
synthesis, probably occurring through decreasing leucine
oxidation and increasing lipolysis. Growth hormone also
potentially blunts insulin proteolytic action and increases free
fatty acid availability, both of which may have a sparing effect
on the amino acid pool.
However, the most potent anabolic effects of hGH may
be related to its role in amino acid metabolism. In a study
of exogenous GH infusion, Copeland and Nair (121) reported
that an acute local infusion of hGH in healthy men
immediately inhibited whole body leucine oxidation
Figure 6. Summary of the signaling responses to resistance exercise. Resistance exercise stimulates muscle fiber contraction and invokes endocrine and immune
responses that subsequently activate satellite cells. These various signals stimulate transcription and translation and, over time, muscle hypertrophy.
Corresponding increases in satellite cell–derived myonuclei accompany fiber hypertrophy. Akt = protein kinase B; AR = androgen receptor; GH = growth
hormone; IGF-1 = insulin-like growth factor-1; JAK = Janus kinase; MAPKs = mitogen-activated protein kinases; mTOR = mammalian target of rapamycin; PI-3K =
phosphatidylinositol-3-kinase; p70 S6K = 70-kDa ribosomal protein S6 kinase; 4E-BP1 = eukaryotic initiation factor 4E binding protein-1. Adapted from Spiering
et al. (470).
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independent of other hormones. In contrast to this finding,
others have reported that local skeletal muscle protein uptake
occurred in response to local hGH infusion in the forearm,
but total body protein metabolism was not affected (197).
Furthermore, it appears that uptake by local contractile
muscle also occurs, with differences in arteriovenous concentrations reported in at least one exercise study (79). However,
the independent effects of GH on amino acid metabolism
remain controversial, as other GH-mediated hormones such
as IGF-1 may also play a significant role (362).
History of the Use of Human Growth Hormone as an
Ergogenic Aid in Athletes
Human growth hormone was first prepared in the 1940s and
in such small amounts that there was likely virtually none
available for athletic performance (321). It is only the human
(and monkey) pituitary GH that has efficacy in man and thus
none of the other species’ GH can be used (297). With the
synthesis of recombinant hGH (rhGH) in the 1980s, a virtually unlimited supply became available, and clinical studies
were undertaken in children and adolescents with subnormal
growth and adults with GH deficiency, aging, and for performance or aesthetic purposes (see below). The evidence
for rhGH to produce salutary ergogenic and performance
effects among athletes is neither robust nor clear (324,539).
What Is the Clinical Role of Growth Hormone?
Growth hormone is administered to promote linear growth in
short children. The following are the Food and Drug
Administration (FDA)–approved indications for GH:
GH deficiency
CKD
Turner syndrome
Small-for-gestational-age infants who fail to catch-up to the
normal growth percentiles
Prader-Willi syndrome
Idiopathic short stature
SHOX gene haploinsufficiency
Noonan syndrome
The most common efficacy outcome in infants, children,
and adolescents is an increase in linear growth, although it
prevents hypoglycemia in some infants with congenital
hypopituitarism.
Growth hormone is administered to promote physiologic
and psychological well-being and altered body composition
in adults with GH deficiency, muscle wasting due to
HIV/AIDS, and short bowel syndrome. All other use is
‘‘off-label’’ and has become of intense interest in the sporting
world, especially earlier this year with the Congressional
hearings related to Major League Baseball.
What Types of Clinical Research Are Being Done With GH?
Clinical research with GH in children is mainly about
promoting growth in various pathological conditions, which
may stunt growth. In some syndromes, for example, the
Prader-Willi syndrome, the alterations in body composition
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(lean body mass, fat mass, and especially the regional
distribution of body fat) are being investigated.
For the adult, the bulk of GH research involves the study of
2 opposite conditions:
1. Growth hormone deficiency to note the changes in wellbeing, body composition as noted above, and the
psychosocial issues of well-being because the major
indication for GH treatment in GH-deficient adults is to
favorably alter the sense of health-related well-being (244).
2. Growth hormone excess (acromegaly) to note the changes
in body composition and health-related well-being, but
especially the alteration of cardiovascular risk factors noted
with diminishing the GH values by surgery, radiotherapy,
and pharmacologic agents (93).
GH Abuse
Growth hormone is listed under class S2 of hormones and
related substances in terms of the 2006 prohibited list. Other
peptides in this category include EPO and corticotrophin
(ACTH) in addition to IGF-1 and insulin. Growth hormone is
likely being abused at increasingly prevalent rates, but before
describing some of the data, it should be noted that much of
what is purported to be hGH, especially on the Internet is not.
Of course, any drug taken orally cannot be hGH. Many of the
products advertised on the Internet and in magazines are
hGH releasers—mainly amino acids and rarely, analogues of
hGH-releasing hormone (435). The notion that amino acids
release hGH is on solid scientific ground, given that tests for
GH sufficiency may include arginine or the closely related
amino acid, ornithine. What is not stated is that very
concentrated solutions of these amino acids are administered
intravenously before GH is released. Also not prominent
(note that these are dietary supplements and not subject to
FDA oversight) is the physiologic concept of the absolute
and then relative refractory period after GH release,
irrespective of the cause.
There are many reports that note an increasing prevalence
of hGH abuse. These come (mainly) from anecdotal reports
including ‘‘information’’ of benefits, from the Internet, a very
favorable write-up in The Underground Steroid Handbook, and
an increasing number of seizures from elite athletes including
cyclists and swimmers. What is it that athletes wish to obtain
from administering hGH? The athletes wish improved
performance, but such studies are difficult to do, either as
‘‘clinical trials’’ or observational studies in athletes; for they
rarely take agents singularly but often a ‘‘cocktail’’ of dietary
supplements and 1 or more doping agents. Although hGH
has not been shown to unequivocally increase muscle
strength or to improve performance (324), it is considered
one of the drugs of choice because it is extremely difficult to
prove that one is receiving it (more about the ‘‘window of
detectability’’ later). The structure of rhGH is identical to
that of the main isoform of natural hGH; it is secreted in
pulsatile manner, meaning that its levels fluctuate widely,
from undetectable to clearly in the ‘‘doping’’ range with
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a short half-life in the circulation. Exercise is potent stimulus
to hGH release, and release may be modified by variations
in nutrition and legitimate nutritional supplements, as
noted previously.
Liu et al. (324) have systematically reviewed the effects of
hGH on athletic performance. Using proper and stringent
criteria for a meta-analysis, they reviewed 7,599 titles from
the largest databases, reviewed 252 abstracts in detail, and
retrieved 56 articles for full-text evaluation. Following their
review, just 44 articles representing only 27 unique studies
met the strict inclusion criteria. The majority of the 303
participants received hGH for an average of 20 days, with
a number having received hGH for only 1 injection. They
were mainly young men (average age 27 years) and were
recreational not elite athletes. The average dose was 36
mgkg21day21, approximately 5- to 10-fold the therapeutic
dose in adults with GH deficiency.
Lean body mass increased in the hGH-treated groups
compared with those not treated [2.1 kg (95% CI, 1.3 to
2.9 kg)], with a small but not statistically significant decrease
in fat mass (20.9 kg [CI 21.8 to 20.0 kg]). Body weight did
not change significantly. Only 2 studies appropriately
evaluated change in strength (142,550). These were the
longest trials of 42 and 84 days. On 1RM voluntary strength
testing, those receiving hGH showed no change in biceps
strength (20.2 kg [CI 21.5 to 1.1 kg]) or quadriceps strength
(20.1 kg [CI 21.8 to 1.5 kg]). In the second study, none of
the 7 other muscle groups evaluated showed a positive
change in strength.
Minor effects of hGH have been noted on basal metabolism
with a slight decrease in respiratory exchange rate reflecting
the preferential burning of fat rather than carbohydrate at rest.
Additionally, there is very little effect on exercise capacity.
The 6 studies evaluated used quite different protocols, and the
results may be summarized as noting that lactate levels
trended higher and that plasma free fatty acid concentrations
and glycerol concentrations were significantly increased,
reflecting the lipolytic metabolic effect of hGH, but the
respiratory exchange ratio did not change.
These studies showed very little ergogenic effects of
administered hGH in recreational athletes. They were of
short duration and unlikely represent how elite athletes
administer hGH, with reference to dose, duration, or other
supplements, either legal or illegal. It is clear that many
athletes abuse steroids in addition to the ‘‘noted’’ amounts
of hGH. None of the studies would have been able to detect
differences of 0.5–1.0% in ‘‘performance.’’ These small
differences are those that are relevant to the time (track
events), distance, or height (field events) that separate the
champion from any other finishing position.
Recently, hGH (19 mgkgd21) of 1 week’s duration was
noted to increase strength, peak power output, and IGF-1
levels in a group of abstinent dependent users of anabolicandrogenic steroids (211). Great care was taken to be certain
that no anabolic steroids were detected in appropriately
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obtained urine samples. Body weight increased (likely water
retention) as did peak power output. This is a very special
group of athletes and is a single study, but it was quite
carefully performed.
Adverse events were common in the larger group of studies
and mirrored those of adult subjects administered hGH in
what were at that time, child and adolescent doses. These
included soft tissue edema, joint pain, carpel tunnel syndrome,
and excessive sweating. Most are related to fluid retention and
considered to be secondary to the GH effect on salt and water
balance by the kidney.
Virtually all studies examining hGH supplementation
had significant methodological limitations. These included
limited examinations on strength and exercise capacity, short
duration of supplementation, and doses not consistent with
the method used by most athletes. Liu et al. (324) suggested
that ‘‘Claims regarding the performance-enhancing properties of growth hormone are premature and are not supported
by our review of the literature. The limited published data
evaluating the effects of growth hormone on athletic
performance suggest that although growth hormone increases lean body mass in the short term, it does not appear
to improve strength and may worsen exercise capacity. In
addition, growth hormone in the healthy young is frequently
associated with adverse events.’’
Detection of GH Abuse
This has been quite a difficult task for the analytical chemists
because the amino acid sequence of recombinant GH is
identical to that of the main GH isoform secreted by the
pituitary: unlike other peptide hormones, it has no N-linked
glycosylation sites; its secretion is pulsatile with a short
half-life (16–20 minutes); there are circulating GH-binding
proteins; potential cross-reactivity with other peptide
hormones (e.g., prolactin); and it is stimulated by exercise
and stress. Blood sampling is required for all detection
methods because less than 0.1% may be found in the urine. Its
renal secretion is poorly understood and highly variable
within and between subjects (250).
The analytical approaches rely on immunoassays as
opposed to the more established doping tests for anabolic
steroids, which depend on GC/MS technology. There are 2
general approaches to detection of doping with rhGH. The
first approach (direct) measures the GH isoform composition
by the differential immunoassay method (70). For this
approach, one constructs pairs of antibodies whose primary
focus is ‘‘all’’ of the isoforms of hGH and a second set that is
virtually restricted to the 22-kDa isoform—the one that is
100% of the recombinant hGH. The first assay is called
‘‘permissive’’ (pituitary) and the second, specific (recombinant). The principle (rationale) is that the more one takes the
rhGH (22 kDa), the less pituitary hGH (especially, 20 kDa)
will be secreted, meaning that the ratio of the specific to the
pituitary will rise. As an example, the ratio rises from 0.6 to
1.5 in subjects administered rhGH, but this assay would only
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be valid within a few days of the last injection of rhGH. The
validation of this technique requires knowledge (testing) of
the effects of exercise on the recombinant to pituitary ratio,
an independent confirmatory test (see below), knowledge of
the ‘‘window of opportunity,’’ and data from athletes, both
recreational and elite. This method is unable to detect doping
with pituitary-derived hGH or the abuse of the GH secretagogues, IGF-1 itself or in combination with its major circulating binding protein, IGFBP-3 (IGF-1/IGFBP-3) (250).
The second is the indirect approach in which specific
analytes dependent on hGH (or IGF-1) would be measured.
Variables from the IGF system and collagen/bone have been
chosen because they change markedly during rhGH
administration, and it appears that combinations of variables
using discriminant functions are the most promising. Detection of rhGH supplementation is possible at least until
2 weeks after the last administration, although there is
progressively decreasing sensitivity after the first week.
Normative data in athletes have been established (233).
The physiological changes in GH-dependent markers in
adolescent athletes are far more dramatic than in older
athletes, thus making it quite difficult to detect in this age
range without constructing a complex algorithm that would
depend more on maturational age than it would on the
chronological age—another complication for doping control.
Data using this approach have noted only minor effects due
to trauma, micro-injury, or ethnic background (166). As with
any assay, rigorous standardization is required and interference by concomitant drug abuse, especially anabolic
steroids, is a likely complication. For the moment, the most
informative combination of analytes is IGF-1 and procollagen III peptide levels and individual discriminant functions
for men and women.
Direction of Future Research
Future research in the doping detection field will require the
determination of combinations of GH-dependent analytes
that are longer lasting than the ones currently used and
perhaps other methods for the direct determination of the
IGFs and GH secretagogues. It would seem that use of
hGH (or other peptide hormones) manufactured by the
major pharmaceutical companies around the world could be
markedly diminished by adding, for example, an inert fluorescent marker that would be excreted in the urine. Detection of
that (unnatural) marker might then be considered a doping
offense. We suspect that that would markedly diminish but
not stop doping offenses with these hormones.
The era of gene doping, for example, adding hGH or IGF-1
genes to specific muscles, is upon us. Experiments have
been done in animals (37). No detection methods presently
available could detect this type of doping.
Legal Issues
As is true for many legitimate drugs, physicians may prescribe
off-label, meaning that trials for that particular condition have
not been performed, but that it is ‘‘logical’’ to use a particular
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already approved drug for a specific patient. Recombinant
hGH is quite different. It is illegal to prescribe hGH off-label
for age-related conditions (anti-aging) or performance enhancement. Unlike most FDA-approved medications, hGH
can only be prescribed for indications specifically authorized by
the Secretary of Health and Human Services (for indications,
see above). In addition, hGH is not considered a ‘‘dietary
supplement’’ and is not subject to the DSHEA legislation
because it is not administered orally and it had formerly been
classified as a ‘‘drug’’ [FDCA 21 USC 321 (ff ) (2) (A) (i)].
The precise language of the FDCA under section 303 [333]
follows:
(f ) (1) Except as provided in paragraph (2), whoever knowingly
distributes, or possesses with intent to distribute, human
growth hormone for any use in humans other than the
treatment of a disease or other recognized medical condition,
where such use has been authorized by the Secretary of
Health and Human Services under section 505 and
pursuant to the order of a physician, is guilty of an offense
punishable by not more than 5 years in prison, such fines
authorized by title 18, or both.
(2) Whoever commits any offense set forth in paragraph (1) and
such offense involves an individual under 18 years of age is
punishable by not more than 10 years imprisonment, such
fines as are authorized by title 18 or both.
(3) Any conviction for a violation of paragraphs (1) and (2) of this
subsection shall be considered a felony violation of the
Controlled Substances Act for the purposes of forfeiture
under section 413 of such Act.
(4) As used in this subsection the term ‘‘human growth hormone’’
means somatrem, somatropin, or an analogue of either of them.
(5) The Drug Enforcement Administration (DEA) is authorized
to investigate offenses punishable by this subsection.
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